BRPI0713253A2 - pde4 inhibition method, method of treating a pde4-mediated disease, compound and pharmaceutical composition - Google Patents

Abstract

PDE4 INHIBITION METHOD, PDE4 MEDIATED TREATMENT METHOD, COMPOUND AND PHARMACEUTICAL COMPOSITION. The present invention relates to compounds and methods that may be useful as inhibitors of phosphodiesterase 4 (PDE4) for the treatment or prevention of inflammatory diseases and other diseases involving high levels of cytokines and pro-inflammatory mediators.

Description

PDE4 INHIBITION METHOD, METHOD OF TREATING A PDE4-MEDIATED DISEASE, COMPOUND AND PHARMACEUTICAL COMPOSITION

Described herein are novel potent and selective bicyclic heteroaryl compounds, of which certain compounds have already been found to be useful as phosphopodiesterase 4 (PDE4) inhibitors, compositions comprising them, and their application as pharmaceuticals for treating the disease. Methods of inhibiting PDE4 activity are also provided, as are methods for treating inflammatory diseases and other diseases involving high levels of cytokines and proinflammatory mediators.

Chronic inflammation is a complication of multifactorial disease characterized by the activation of multiple types of inflammatory cells, for example, lymphoid lineage cells (including T lymphocytes) and myeloid lineage cells (including granulocytes, macrophages, and monocytes). Proinflammatory mediators, including cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-I), are produced by these activated cells. Accordingly, an agent that suppresses the activation of these cells or their production of proinflammatory cytokines would be useful in the therapeutic treatment of inflammatory diseases and other diseases involving high levels of cytokines.

Cyclic adenosine monophosphate (cAMP) is a second messenger that mediates the biological responses of cells to a wide range of extracellular stimuli. When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated to convert adenosine triphosphate (ATP) to cAMP. It is theorized that cAMP agonist induced actions within the cell are predominantly mediated by cAMP-dependent protein kinase action. Intracellular cAMP actions are terminated either by a nucleotide transport to the outside of the cell or by enzymatic cleavage by cyclic nucleotide phosphodiesterases (PDEs), which hydrolyzes the 3'-phosphodiester bond to form '5-adenosine monophosphate (5'- AMP). 5'-AMP is an inactive metabolite

The PDE superfamily is subdivided into two main classes, class I and class II, which have no recognizable sequence of similarity. Class I includes all known mammalian PDEs and is comprised of 11 identified families that are separate gene products. Some PDEs are highly specific for cAMP hydrolysis (PDE4, PDE7, PDE8), some are highly cGMP-specific (PDE5, PDE6, PDE9), and some have mixed specificity (PDE1, PDE2, PDE3, PDE10, PDE11). All characterized mammalian PDEs are dimeric, but the importance of dimeric structure for function in each of the PDEs is unknown.

The PDE4 subfamily is comprised of 4 members: PDE4A, PDE4B, PDE4C and PDE4D. These enzymes have N-terminal regulatory domains that presumably mediate dimerization, which results in the best regulated PDE activity. In addition, activity is regulated through the cAMP-dependent protein kinase phosphorylation sites in this underlying regulatory domain. PDE4 enzymes are widely expressed and distributed.

Elevated levels of cAMP in human myeloid and lymphocyte cell line are associated with suppression of cell activation. The intracellular enzyme family of PDEs therefore regulates the level of cAMP in cells. PDE4 is a predominant isotype of PDE in these cells, and is a major contributor to cAMP degradation. Accordingly, inhibition of PDE function would prevent the conversion of the camp to the inactive metabolite 5 - AMP and, therefore, maintaining higher levels of cAMP, and, accordingly for cell suppression.

PDE4 inhibitors have been shown to inhibit TNFα production and to partially inhibit IL-β release by monocytes (see Semmler et al, Int. J.

Immunopharmacol., 15, pp. 409-413 (1993); Molnar-Kimber et al., Mediators of Inflammation, 1, pp. 411-417 (1992)). PDE4 inhibitors have also been shown to inhibit superoxide radical production of human polymorphonuclear leukocytes (see Verghese et al, J. Mol.

Cell Cardiol., 21 (Suppl. 2), S61 (1989); Nielson et al., J. Allergy Immunol, 86, pp. 801-808 (1990)); to inhibit the release of amines and vasoactive prostanoids from human basophils (see Peachell et al, J ". Immunol., 148, pp. 2503-2510, (1992)); to inhibit respiratory explosions in eosinophils (see Dent et al. J. Pharmacol., 103, pp. 1339-1346, (1991)), and to inhibit activation of human T-lymphocytes (see Robicsek et al., Biochem. Pharmacol., 42, pp. 869-877, (1991)). ).

Inflammatory cellular activation and excessive or unregulated cytokine production (eg TNFα and IL-Iβ) are implicated in allergic, autoimmune and inflammatory diseases and disorders such as rheumatoid arthritis, osteoarthritis, gouty arthritis, spondylitis. , thyroid-associated ophthalmopathy, Behcet's disease, sepsis, septic shock, endotoxic shock, gram negative sepses, gram positive sepsis, toxic shock syndrome, asthma, chronic bronchitis, adult respiratory distress syndrome, chronic pulmonary inflammatory disease such as, chronic obstructive pulmonary disease, silicosis, pulmonary sarcoidosis, myocardial reperfusion injury, brain and extremities, fibrosis, cystic fibrosis, keloid formation, scar formation, atherosclerosis, graft rejection disorders such as graft versus allograft rejection or host rejection, chronic glomerulonephritis, lupus, inflammatory bowel disease o, such as Crohn's disease and ulcerative colotes, proliferative lymphocyte diseases such as leukemia, ophthalmological diseases such as dry eye and eye pain resulting in inflammation surgery and inflammatory dermatoses such as atopic dermatitis, psoriasis and urticaria.

Other conditions characterized by elevated cytokine levels include brain injury due to moderate trauma, cardiomyopathy such as congestive heart failure, cachexia, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), ARC (complex fever, myalgias of fever due to infection, cerebral malaria, bone resorption diseases and osteoporosis, keloid formation, scar tissue formation, and pyrexia.

Additionally, several properties of TNFα, such as collagenase stimulation, stimulation of angiogenesis in vivo, stimulation of bone reabsorption, and an ability to increase tumor cell adherence to endothelium, are consistent with a role for TNF in metastatic development and spread. of cancer in the host. TNFα has recently been directly implicated in promoting tumor cell growth and metastasis (see, Orosz et al., J. Exp. Medl 177, pp. 1391-1398, (1993)).

Research has been shown to be of considerable interest in the use of PDE4 inhibitors as anti-inflammatory agents. Early evidence indicates that PDE4 inhibition has beneficial effects on a variety of inflammatory cells, such as monocytes, macrophages, Th-I lineage T-cells, and granulocytes. The synthesis and / or release of many proinflammatory mediators such as cytokines, lipid mediators, superoxide and biogenic amines such as histamines have been attenuated in these cells by the action of PDE4 inhibitors. PDE4 inhibitors also affect other cellular functions including Τ cell proliferation, granulocyte transmigration in response to chemotoxic substances, and the integrity of cell endothelial junctions within the vasculature.

The model, synthesis and selection of the various PDE4 inhibitors have been reported. Methylxanthines such as caffeine and theophylline were the first PDE inhibitors discovered, but

These compounds are non-selective with respect to which PDE is inhibited. The drug rolipram, an antidepressant agent was one of the first reported specific PDE4 inhibitors, with a reported IC50 of approximately 200 nM with respect to inhibition of recombinant human PDE4.

Researchers continued to search for

PDE4 inhibitors that are more selective with regard to inhibiting PDE4, which had a lower IC50 than rolipram and which avoided the undesirable central nervous system (CNS) side effects such as nausea, vomiting and sedation associated with the administration of PDE4. rolipram. In addition, several companies are now undertaking clinical trials of other PDE4 inhibitors. However, problems with efficacy and adverse side effects such as emesis and central nervous system disorders remain unresolved.

Accordingly, compounds which selectively inhibit PDE4 and which reduce or eliminate adverse side effects associated with previous PDE4 inhibitors would be useful in the treatment of allergic and inflammatory diseases and other diseases associated with excessive or unregulated cytokine production, such as, TNF. In addition, selective PDE4 inhibitors would be useful in treating diseases that are associated with elevated cAMP levels or PDE4 function in a particular target tissue.

Novel compounds and pharmaceutical compositions useful as anti-inflammatory agents through PDE4 inhibition have been found, along with methods of synthesizing and using compounds that include methods for inhibiting PDE4 in a patient by administering the compounds.

Disclosed herein is a class of compounds, certain to have been found to be useful in the treatment of PDE4-mediated diseases and conditions, defined by Structural Formula I:

Where:

A is an optionally substituted saturated or unsaturated hydrocarbon chain or a heteroatom-containing hydrocarbon chain having 3 to 5 atoms forming five to seven membered rings;

U, and V are independently selected from the group consisting of O, N (R7) and SOq;

R1 and R2 are independently selected from the group consisting of hydrogen, - (CH2) SG1G2G3, acyl, aclalkyl, carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, ether, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen and hydroxyalkyl, any of which may optionally be substituted;

s is 0-8;

G1 is selected from the group consisting of alkoxy, amino, starch, carbonyl, hydroxy, ether, amino acid and null;

G 2 is selected from the group consisting of alkyl, alkoxy, amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino, guanidine, amino acid and zero of which may be optionally substituted;

G3 is selected from the group consisting of alkyl, alkoxy, amino, hydroxy, ether, carboxy, hydroxamic acid, amino acid, phosphonate, phosphoamido, and null, of which may be

optionally substituted;

R3 and R4 are each independently selected.

from the group consisting of hydrogen, halogen, alkoxy and lower alkyl;

8 9

R5 is selected from the group consisting of - (CR R)

mW (CR10R11) n- and - (CR12R13) P-;

m, n, and q are each independently 0, 1 or 2;

ρ is 1 or 2;

W is selected from the group consisting of O, N (R7),

C (O) N (R 7) and SOq;

R6 is selected from the group consisting of carboxy,

alkylcarboxy, starch, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, acyl, hydroxamic acid of which may be optionally substituted;

R 7, R 8, R 9, R 10, R 11 / R 12 and R 13 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, amino, aminoalkyl, aminoalkoxy and hydrogen and optionally

replaced by lower alkyl.

Certain compounds according to the present invention have utility of PDE4 modulating or inhibiting activity, and may be used in the treatment or prophylaxis of a disease or condition in which PDE4 has an active role. Thus, in broad aspect, certain embodiments of the present invention also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods of producing and using the compounds and compositions. Certain embodiments of the present invention provide PDE4 inhibition methods. Other embodiments of the present invention provide methods of treating a PDE4-mediated disease in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of the compound or composition according to the present invention. Related embodiments disclose the use of certain compounds disclosed herein as therapeutic agents, for example, in the treatment of inflammatory diseases and other diseases involving high levels of cytokines and proinflammatory mediators. The present invention also contemplates the use of certain compounds disclosed herein for use in the manufacture of a medicament for treating a disease or condition by inhibiting PDE4.

In further embodiments, the compounds of the present invention have Formula II

<formula> formula see original document page 9 </formula>

where: X1 is NR14; X 2 is selected from the group consisting of C (O), (CR 15 R 16) and null;

X3 is selected from the group consisting of C (O), N (R17) and (CR18 R19);

R 1 and R 2 are independently selected from the group consisting of hydrogen, - (CH 2) SG 1 G 2 G 3, acyl, acylalkyl, carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkynyl, carboxy, carboxyalkyl, ether, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen and hydroxyalkyl, any of which may optionally be substituted;

s is 0-8;

G1 is selected from the group consisting of alkoxy, amino, starch, carbonyl, hydroxy, ether, amino acid and null;

G 2 is selected from the group consisting of alkyl, alkoxy, amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino, guanidine, amino acid and zero of which may be optionally substituted;

G 3 is selected from the group consisting of alkyl, alkoxy, amino, hydroxy, ether, carboxy, hydroxamic acid, amino acid, phosphonate, phosphoamido, and null, of which may be optionally substituted;

R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, alkoxy and lower alkyl;

R5 is selected from the group consisting of - (CR8R9) mW (CR10R11) n- and - (CR12R13) p. ;

m, n, and q are each independently 0, 1 or 2;

ρ is 1 or 2;

W is selected from the group consisting of O, N (R7), C (O) N (R7) and SOq;

R 6 is selected from the group consisting of carboxy, heterocycloalkyl, alkyl, heteroalkyl, acyl, hydroxamic acid from which it may be optionally substituted;

R 7, R 8, R 9, R 10, R 11, R 12 and R 13 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, amino, aminoalkyl, aminoalkoxy and hydrogen and optionally substituted by lower alkyl;

R14 and R17 are independently selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, hydroxyalkyl, haloalkyl and aminoalkyl and a binder; and

R15, R16, R18 and R19 are each independently selected from the group consisting of hydrogen, halogen, lower alkyl, haloalkyl, alkoxy, haloalkoxy, amino, aminoalkyl, aminoalkoxy and a bond.

In further embodiments, the compounds of the present invention have Formula III

<formula> formula see original document page 11 </formula>

alkylcarboxy, starch, aryl, heteroaryl, cycloalkyl,

Rs (IlI)

Where:

X1 is NR14;

X 2 is selected from the group consisting of C (O) and null;

X3 is selected from the group consisting of C (O) and (CR18 R19);

R1 and R2 are independently selected from the group consisting of hydrogen, - (CH2) SG1G2G3, acyl, aclalkyl, carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl,

amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, ether, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclealkyl, heterocycloalkylalkyl, aryl, guanidine, heteroaryl, heteroaryl and hydroxy which may optionally be substituted;

s is 1-8;

G1 is selected from the group consisting of alkoxy, amino, starch, carbonyl, hydroxy, ether, amino acid and null;

G 2 is selected from the group consisting of alkyl, alkoxy, amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino, guanidine, amino acid and zero of which may be optionally substituted;

G3 is selected from the group consisting of alkyl, alkoxy, amino, hydroxy, ether, carboxy, hydroxamic acid, amino acid, phosphonate, phosphoamido, and null, of which may be

optionally substituted;

R3 and R4 are each independently selected.

of the group consisting of hydrogen, halogen, alkoxy and

lower alkyl;

R5 is selected from the group consisting of - (CR8R9)

mW (CR10R11) n- and - (CR12R13) P-;

m, n, and q are each independently 0, 1 or 2;

ρ is 1 or 2;

W is selected from the group consisting of O, N (R7),

C (O) N (R 7) and SOq;

R6 is selected from the group consisting of carboxy,

alkylcarboxy, starch, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, acyl, hydroxamic acid of which may be optionally substituted;

R 8, R 9, R 10, R 11, R 12 and R 13 are each independently selected from the group consisting of hydrogen and optionally substituted by lower alkyl;

R14 and R17 are independently selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, hydroxyalkyl, haloalkyl and aminoalkyl; and

R15, R16, R18 and R19 are each independently selected from the group consisting of hydrogen, halogen, lower alkyl, haloalkyl, alkoxy, haloalkoxy, amino, aminoalkyl, aminoalkoxy and a bond.

In certain embodiments, the compounds of the present invention have the formula IV

R4 ff

Re (IV)

where: X3 is (CR18 R19);

R1 and R2 are independently selected from the group consisting of hydrogen, - (CH2) sGxG2G3, acyl, aclalkyl, carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkynyl, carboxy, carboxyalkyl, ether, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen and hydroxyalkyl, any of which may optionally be substituted;

s is 1-8; G1 is selected from the group consisting of alkoxy, amino, starch, carbonyl, hydroxy, ether, amino acid and null;

G 2 is selected from the group consisting of alkyl, alkoxy, amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino, guanidine, amino acid and zero of which may be optionally substituted;

G 3 is selected from the group consisting of alkyl, alkoxy, amino, hydroxy, ether, carboxy, hydroxamic acid, amino acid, phosphonate, phosphoamido, and null, of which may be optionally substituted;

R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, alkoxy and lower alkyl;

R5 is selected from the group consisting of - (CR8R9)

mW (CR10R11) n- and - (CR12R13) p. ;

m, n, and q are each independently 0, 1 or 2;

ρ is 1 or 2;

W is selected from the group consisting of O, N (R7), C (O) N (R7) and SOq;

R 6 is selected from the group consisting of carboxy, alkylcarboxy, starch, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, acyl, hydroxamic acid from which it may be optionally substituted;

R 8, R 9, R 10, R 11, R 12 and R 13 are each independently selected from the group consisting of hydrogen and optionally substituted by lower alkyl;

R 7 and R 14 are independently selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, hydroxyalkyl, haloalkyl and aminoalkyl; and

R18 and R19 are each independently selected from the group consisting of hydrogen, halogen, lower alkyl, haloalkyl, alkoxy, haloalkoxy, amino, aminoalkyl, aminoalkoxy and a bond. In further embodiments, the compounds of the present invention have Formula V

(V) <formula> formula see original document page 15 </formula> where:

R1 and R2 are independently selected from the group.

consisting of hydrogen, - (CH2) SG1G2G3i acyl, acalkyl, carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, ether, heteroalkyl, haloalkylcycloalkyl, cycloalkyl heterocycloalkylalkyl, aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen and hydroxyalkyl, any of which may optionally be substituted; s is 1-8;

G1 is selected from the group consisting of alkoxy, amino, starch, carbonyl, hydroxy, ether, amino acid and null;

G 2 is selected from the group consisting of alkyl, alkoxy, amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino, guanidine, amino acid and zero of which may be optionally substituted;

G 3 is selected from the group consisting of alkyl, alkoxy, amino, hydroxy, ether, carboxy, hydroxamic acid, amino acid, phosphonate, phosphoamido, and null, of which may be optionally substituted;

R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, alkoxy and lower alkyl;

R5 is selected from the group consisting of - (CR8R9) mW (CR10R11) n- and - (CR12R13) p. ;

m, n, and q are each independently 0, 1 or 2;

ρ is 1 or 2;

W is selected from the group consisting of O, N (R7), C (O) N (R7) and SOq;

R 6 is selected from the group consisting of carboxy, alkylcarboxy, starch, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, acyl, hydroxamic acid from which it may be optionally substituted;

R 7 and R 14 are independently selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, hydroxyalkyl, haloalkyl and aminoalkyl; and

R19 is selected from the group consisting of hydrogen, halogen, lower alkyl and haloalkyl.

However, in further embodiments compounds are provided wherein R 7 and R 14 are independently selected from the group consisting of hydrogen, halogen and optionally substituted lower alkyl.

In further embodiments compounds are provided wherein R 6 is selected from the group consisting of aryl and heteroaryl, any of which may be optionally substituted;

In some supplementary embodiments compounds are provided where R19 is hydrogen.

However in further embodiments compounds are provided where R 6 is selected from the group consisting of phenyl, pyridine, pyrimidine, pyridazine and pyrazine, of which it may be optionally substituted.

Some additional embodiments are provided compounds where R 6 is selected from the group consisting of phenyl, pyridine and pyrimidine, of which it may be optionally substituted.

However in further embodiments compounds are provided where R 14 is hydrogen.

However in further embodiments compounds are provided wherein: R5 is - (CR8R9) mW (CR10R11) n;

m and η are both 0;

W is N (R7); and

R7 is hydrogen.

However in further embodiments compounds are provided where R 6 has the formula

<formula> formula see original document page 17 </formula>

Where

X4 is CR20 or N

X5 is CR21 or N

X6 is CR22 or N

X7 is CR23 or N

X8 is CR24 or N;

where no more than two of X4 - X8 may be N; and

and R 24 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, amino and carboxyl.

However in additional embodiments compounds are provided where R 6 has a formula selected from the group consisting of However in additional embodiments compounds are provided wherein R 2 is a lower alkyl. However in further embodiments, R 2 is methyl.

However in further embodiments compounds are provided wherein: R1 is selected from the group consisting of (CH2) SG1G2G3, lower alkyl, cycloalkyl, cycloalkylalkyl and a heterocycloalkyl of which may optionally be substituted;

s is 1-6;

G1 is selected from the group consisting of amino, starch and zero;

G 2 is selected from the group consisting of alkoxy, aryl, halo, heterocycloalkyl and zero, of which it may optionally be substituted; and

G3 is selected from the group consisting of alkyl, carboxyl, and null, some of which may optionally be substituted.

In further embodiments, the compounds of the present invention have the structural formula VI where:

R1 and R2 are independently selected from the group consisting of hydrogen, - (CH2) SG1G2G3, acyl, aclalkyl, carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkynyl, carboxy, carboxyalkyl, ether, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen and hydroxyalkyl, any of which may optionally be substituted;

s is 1-8;

G1 is selected from the group consisting of alkoxy, amino, starch, carbonyl, hydroxy, ether, amino acid and null;

G 2 is selected from the group consisting of alkyl, alkoxy, amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino, guanidine, amino acid and zero of which may be optionally substituted;

G 3 is selected from the group consisting of alkyl, alkoxy, amino, hydroxy, ether, carboxy, hydroxamic acid, amino acid, phosphonate, phosphoamido, and null, of which may be optionally substituted;

R20 and R24 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, amino and carboxyl. However in further embodiments, compounds of the present invention have Formula VII

<formula> formula see original document page 20 </formula>

R1 and R2 are independently selected from the group consisting of hydrogen, - (CH2) SG1G2G3, acyl, aclalkyl, carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkynyl, carboxy, carboxyalkyl, ether, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen and hydroxyalkyl, any of which may optionally be substituted;

s is 1-8;

G1 is selected from the group consisting of alkoxy, amino, starch, carbonyl, hydroxy, ether, amino acid and null;

G 2 is selected from the group consisting of alkyl, alkoxy, amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino, guanidine, amino acid and zero of which may be optionally substituted;

G 3 is selected from the group consisting of alkyl, alkoxy, amino, hydroxy, ether, carboxy, hydroxamic acid, amino acid, phosphonate, phosphoamido, and null, of which may be optionally substituted;

R20, R22 and R24 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, amino and carboxyl.

Compounds of the present invention may be selective between PDE4 isoforms PDE4A, PDE4B, PDE4C, and PDE4D in various ways. For example, the compounds described herein may be selective for PDE4B and PDE4D over two other isoforms, be a collective inhibitor of all isoforms, or be selective for only one isoform. In certain embodiments, the compounds of the present invention may be PDE4B selective over other isoforms.

The present invention also relates to a method of inhibiting at least one PDE4 function comprising the step of contacting PDE4 with a compound of formula I as described herein. Cell phenotype, cell proliferation, PDE4 activity, change in biochemical output produced by active PDE4, expression of PDE4, or PDE4 binding with a natural binding partner can be monitored. Such methods may be disease treatment methods, biological assays, cellular assays, biochemical assays, or the like.

As used herein, the terms below have the meanings indicated.

When value ranges are disclosed and the denotation "from ηχ ... to n2" is used, where ni and n2 are the numbers, then, unless otherwise specified, this denotation is intended to include the numbers between them. up and the scale between them. This scale can be integral or continuous between them and including the final values. As an example, the "2 to 6 carbons" scale is intended to include two, three, four, five and six carbons, since the carbons come in whole units. Compare, as an example, the scale "from 1 to 3 μΜ (micromolar)" which is intended to include 1 μΜ, 3μΜ and everything between any number of significant figures (eg 1.255μΜ, 2.1 μΜ, 2.9999 μΜ, etc.).

The term "approximately," as used herein, is intended to qualify the numerical values which it modifies by denoting a value as the variable within a margin of error. When no particular margin of error, such as a standard deviation at a given mean value in a chart or data table, is reported, the term "approximately" shall be understood to mean that scale that would encompass the reported value and the scale that would be included by rounding up or down to this figure as well, taking into account significant figures.

The term "acyl," as used herein, alone or in combination, refers to a carbonyl attached to an alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl or any other group wherein the carbonyl-attached atom is carbon. An "acetyl" group, which is an acyl type, refers to - group - C (O) CH 3. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group attached to a parent molecular group through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl and aroyl.

The term "alkenyl" as used herein, alone or in combination, refers to a straight chain or branched chain hydrocarbon radical that has one or more double bonds and contains 2 to 20 carbon atoms. In certain embodiments, said alkenyl will comprise 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bonding system joined at two or more positions, such as ethenylene [(-CH = CH-), (-C :: C)]. Examples of suitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwise specified, the term "alkenyl" may include "alkenylene" groups. The term "alkoxy" as used herein, alone or in combination, refers to an alkyl ether radical, where the term alkyl is as defined below. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.

The term "alkyl" as used herein, alone or in combination, refers to a straight chain or branched chain alkyl radical containing 1 to 20 carbon atoms. In certain embodiments, said alkyl will comprise 1 to 10 carbon atoms. In further embodiments, such alkyl will comprise 1 to 6 carbon atoms. Alkyl groups may optionally be substituted as defined herein. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl, noyl and the like. The term "alkylene," as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight chain or branched chain saturated hydrocarbon joined at two or more positions, such as methylene (-CH 2 -). Unless otherwise specified, the term "alkyl" may include "alkylene" groups.

The term "alkylamino," as used herein, alone or in combination, refers to an alkyl group attached to a parent molecular group through an amino group. Suitable alkylamino groups may be mono or dialkylated to groups such as, for example, N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-ethylmethylamino and the like.

The term "alkylidene" as used herein alone or in combination refers to an alkenyl group in which the carbon atom of the carbon-carbon double bond belongs to the group to which the alkenyl group is attached. The term "alkylthio," as used herein, alone or in combination, refers to an alkyl thioether (R-S-) radical where the term alkyl is as defined above and where sulfur may be single or double oxidized. Examples of suitable alkyl thioether radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl and the like.

The term "alkynyl" as used herein, alone or in combination, refers to a straight chain or branched chain hydrocarbon radical that has one or more triple bonds and contains 2 to 20 carbon atoms. In certain embodiments, such alkynyl comprises 2 to 6 carbon atoms. In further embodiments, such alkynyl comprises 2 to 4 carbon atoms. The term "alkynylene" refers to a carbon-carbon triple bond joined at two positions, such as ethinylene (-C ::ileno:C ::C =C,). Examples of alkynyl radicals include ethinyl, propynyl, hydroxypropynyl, butin-1-yl, butin-2-yl, pentin-1-yl, 3-methylbutin-1-yl, hexin-2-yl and the like. Unless otherwise specified, the term "alkynyl" may be

include "alkynylene" groups.

The terms "starch" and "carbamoyl," as used herein, alone or in combination, refer to a starch group as described below attached to a parent molecular group through a carbonyl group or vice versa. The term "-C starch" as used herein, alone or in combination, refers to a group -C (= O) -N (R) 2 with R as defined herein. The term N starch "as used herein, alone or in combination, refers to a group RC (= 0) N (R '), with ReR' as defined herein. The term" acylamino "as used herein, alone or in combination, it comprises an acyl group attached to a parent group through an amino group An example of an "acylamino" group is acetylamino (CH 3 C (O) NH-).

The term "amino," as used herein, alone or in combination, refers to - N (R) (R ') or -N (R) (R') (R ''), where R, R 'and R "are independently selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl which may itself optionally be substituted.

The term "amino acid," as used herein, alone or in combination, means a form substituent - NRCH (R1) C (O) OH, where R is typically hydrogen, but may be cyclized with N (e.g., as in the case from the amino acid proline) and R is selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroarl, amino, starch, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, aminoalkyl, amidoalkyl, hydroxyalkyl, thioalkyl, thioalkyl and alkylthio, any may optionally be substituted. The term "amino acid" includes all natural amino acids as well as synthetic analogs.

The term "aryl" as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings where such rings may be joined together in a pendant manner or may be fused. The term; "aryl" embraces aromatic radicals such as benzyl, phenyl, naphthyl, anthracenyl, phenanthryl, indanyl, indenyl, anulenyl, azulenyl, tetrahydronaphthyl and biphenyl.

The term "arylalkenyl" or "aralkenyl," as used herein, alone or in combination, refers to an aryl group attached to a parent molecular group through an alkenyl group. The term "arylalkoxy" or "aralkoxy," as used herein, alone or in combination, refers to an arylaryl group attached to a parent molecular group through an alkoxy group.

The term "arylalkyl" or "aralkyl," as used herein, alone or in combination, refers to an aryl group attached to a parent molecular group through an alkyl group.

The term "arylalkynyl" or "aralquinyl," as used herein, alone or in combination, refers to an aryl group attached to a parent molecular group through an alkynyl group.

The term "arylalkanoyl" or "aralkanoyl" or "aroyl" as used herein, alone or in combination, refers to an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as benzoyl, naphthitoyl, phenylacetyl, phenylpropionyl 3 ( hydrokinamoyl), phenylbutyryl 4, (2-naphthyl) acetyl, chlorohydrocinamoyl 4, and the like. The term aryloxy as used herein, alone or in combination, refers to an aryl group attached to a parent molecular group with an oxide. The terms "benzo" and "Benz," as used herein, alone or in combination, refer to the divalent radical C6H4 = derived from benzene. Examples include benzothiophene and benzimidazole.

The term "carbamate," as used herein, alone or in combination, refers to a carbamic acid ester (-NHCOO-) in which it may be attached to a parent molecular group of nitrogen or acid end, and which may be optionally be substituted as defined herein.

The term "O-carbamyl" as used herein, alone or in combination, refers to an OC (O) NRR 'group, with ReR as defined herein.

The term "N-carbamyl" as used herein, alone or in combination, refers to a group NR1ROC (O), with ReR as defined herein.

The term "carbonyl" as used herein, when alone includes formyl [-C (O) H] and in combination is a group-C (O) - group.

The term "carboxyl" or "carboxyl," as used herein, refers to -C (O) OH, O-carboxy, C carboxy, or the corresponding carboxylate ion, such as a carboxylic acid salt. An "O-carboxy" group refers to an RC (O) group, where R is as defined herein. An "N-carboxy" group refers to a group -C (O) OR where R is as defined herein.

The term "cyan," as used herein, alone or in combination, refers to NC.

The term "cycloalkyl" or alternatively "carbocycle" as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical where each cyclic moiety contains from 3 to 12 members of ring of the carbon atom and which may optionally be a benzo fused ring system which is optionally substituted as defined herein. In certain embodiments, such cycloalkyl will comprise 5 to 7 carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydronaphthyl, 2,3 dihydro-1H-indenyl, adamantyl and the like. "Bicyclic" and "tricyclic" as used herein are intended to include fused ring systems such as decahydronaphitalene, octahydronaphitalene as well as the saturated or partially unsaturated (multicenter) multicyclic type. The latter type of isomer is generally exemplified pentan bicyclo [1,1,1] pentane, camphor, adamantane, and bicyclo [3,2,1] octane.

The term "ester," as used herein, alone or in combination, refers to a carboxyl group linking two carbon-bonded moieties.

The term "ether," as used herein, alone or in combination, typically refers to an oxide group linking two carbon-bonded moieties. The "ether" may also include polyethers, such as - RO (CH2) 2O (CH2) 20 (CH2) 2OR ', - RO (CH2) 20 (CH2) 20R', - RO (CH2) 20R ', and - RO (CH 2) 2 OH.

The term "halo," or "halogen," as used herein, alone or in combination, refers to fluorine, chlorine, bromine or iodine.

The term "haloalkoxy" as used herein, alone or in combination, refers to a haloalkyl group attached to a parent molecular group through an oxygen atom.

The term "haloalkyl," as used herein, alone or in combination, refers to an alkyl radical which has the meaning as defined above where one or more hydrogens are substituted with a halogen. Specifically encompassed are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for example, may have a chlorine, fluorine, iodine or bromine atom within the radical. Dialog and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichlorethyl and dichloropropyl. "Haloalkylene" refers to a haloalkyl group joined at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-FC2-), chloromethylene (-CHCl1) and the like.

The term "etherealkyl" as used herein alone or in combination refers to a straight or branched chain stable cyclic hydrocarbon radical, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of a stable number of carbon atoms and one to three heteroatoms selected from the group consisting of O, N, and S, and where nitrogen and sulfur atoms may optionally be oxidized and nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N, and S may be placed anywhere within the heteroalkyl group. Above two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3. The term heteroalkyl may include ethers.

The term "heteroaryl" as used herein, alone or in combination, refers to 3 to 7 membered unsaturated heteromonocyclic rings, or fused polycyclic rings wherein at least one of the fused rings is unsaturated, where one atom is selected from at least from the group consisting of O, S and N. In certain embodiments, such heteroaryl will comprise from 5 to 7 carbon atoms. The term also encompasses fused polycyclic groups where heterocyclic radicals are fused to aryl radicals, where heteroaryl radicals are fused to other heteroaryl radicals, or where heteroaryl radicals are fused to cycloalkyl radicals. Exemplary heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolylindol, indolylimidazole, benzoylindole, quinolyl, isoquinolyl, quinoxalinyl,

quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, cromonil,

coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl,

thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Examples of tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The terms "heterocycloalkyl" and interchangeably "heterocycle" as used herein, alone or in combination, each refer to monocyclic, bicyclic, or saturated, partially unsaturated, or fully unsaturated heterocyclic radical containing at least one heteroatom as ring members, where each said heteroatom may independently be selected from the group consisting of nitrogen, oxygen and sulfur. In . In certain embodiments, said heterocycloalkyl will comprise 1 to 4 heteroatoms as ring members. In further embodiments, said heterocycloalkyl will comprise 1 to 2 ring members of the heteroatoms. In certain embodiments, said heterocycloalkyl comprises 3 to 8 ring members in each ring. In further embodiments, said heterocycloalkyl will comprise from 3 to 7 ring members in each ring. However, in further embodiments, said heterocycloalkyl will comprise from 5 to 6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include sugars, sulfones, sulfoxides, nitrogen tertiary ring member N-oxides and benzo carbocyclic fused and ring systems; additionally both terms also include systems where a heterocycle ring is fused to an aryl group as defined herein or an additional heterocycle group. Examples of heterocycloalkyl groups include aziridinyl, azetidinyl, 1,3 benzodioxolyl, dihydroisoindolylhydroisoquinolinyl,

dihydrocinolinyl, dihydrobenzodioxinyl, dihydro [1,3] oxazolo [4,5-b] pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3 dioxanyl, 1,4 dioxolyl, 1,3 dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. Heterocycloalkyl groups may optionally be substituted unless specifically prohibited.

The term "hydrazinyl" as used herein, alone or in combination, refers to two amino groups linked by a single bond, that is, -N-N-.

The term "hydroxamic acid" as used herein refers to -C (O) (R) O (R1), where ReR 'are as defined herein, or, including some corresponding salt of hydroxamic acid.

The term "hydroxy" as used herein, alone or in combination, refers to -OH.

The term "hydroxyalkyl" as used herein, alone or in combination, refers to a hydroxy group attached to a parent molecular group through an alkyl group.

The term "imino" as used herein, alone or in combination, refers to = N-.

The term "iminohydroxy" as used herein, alone or in combination, refers to = N (OH) and N-O-.

The term "isocyanate" refers to the NCO group. The term "isothiocyanate" refers to the NCS group. The phrase "straight chain atoms" refers to the longest straight chain of selected atoms independently of carbon, nitrogen, oxygen and sulfur.

The term "minor," as used herein, alone or in combination, means that they contain from 1 to 6 carbon atoms.

The term "mercaptile" as used herein, alone or in combination, refers to an RS- group, where R is as defined herein.

The term "nitro," as used herein, alone or in combination, refers to -NO 2.

The terms "oxy" or "oxa" as used herein, alone or in combination, refer to -O.

The term "oxo," as used herein, alone or in combination, refers to = 0.

The term "perhaloalkoxy" refers to an alkoxy group where all hydrogen atoms are replaced by halogen atoms.

The term "perhaloalkyl" as used herein, alone or in combination, refers to an alkyl group where all hydrogen atoms are replaced by halogen atoms.

The term "phosphoamide" as used herein, alone or in combination, refers to a [(OH) 2 P (O) O-] phosphate group in which one or more of the hydroxyl groups has been replaced by nitrogen, amino or starch.

The term "phosphonate" as used herein, alone or in combination, refers to a group of the form ROP (OR ') (OR) O- where R and R' are selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl cycloalkyl, heteroaryl, and heterocycloalkyl, which may itself optionally be substituted. "Phosphonate" includes phosphate [(OH) 2P (O) O-] and the relative anions of phosphoric acid which may form salts.

The terms "sulfonate", "sulfonic acid" and "sulfonic" as used herein, alone or in combination, refer to the group of SO3H and its anion as sulfonic acid is used in salt formation.

The term "sulfanyl," as used herein, alone or in combination, refers to S.

The term "sulfinyl," as used herein, alone or in combination, refers to -S (O) -.

The term "sulfonyl," as used herein, alone or in combination, refers to S (O) 2. The term N sulfonamido "refers to an RS group

(= (D) 2 NR 'with R and R 1 as defined herein.

The term "S-sulfonamido" refers to a group □ (= 0) 2NRR ', with ReR' as defined herein.

The terms "aunt" and "uncle," as used herein, alone or in combination, refer to an -S group or an ether where oxygen is substituted with sulfur. Oxidized derivatives of the thio group, ie sulfinyl and sulfonyl, are included in the definition of thia and thio.

The term "thiol," as used herein, alone or in combination, refers to a -SH group.

The term "thiocarbonyl," as used herein, when alone including thioformyil - C H and in combination is a -C (S) - group.

The term "N-thiocarbamyl" refers to a group of ROC (S) NR ', with ReR' as defined herein.

The term "O-thiocarbamyl" refers to a group -OC (S) NRR1, with ReR 'as defined herein.

The term "thiocyanate" refers to a group - CNS.

The term "trihalomethanesulfonamido" refers to a group X3CS (O) 2NR- with X being a halogen and an R as defined herein.

The term "trihalomethanesulfonyl" refers to a group X3CS (O) 2 - where X is a halogen.

The term "trihalomethoxy" refers to a group X3CO- where X is a halogen.

The term "trisubstituted silyl" as used herein, alone or in combination, refers to a substituted silicone group at its three free valencies with groups as listed herein under the definition of substituted amino. Examples include trimethylsilyl, tert-butyldimethylsilyl, triphenylsilyl and the like.

Any definition herein may be used in combination with any other definition to describe group of the structural compound. By convention, the dragging element of a definition is one that ties in with the parental grouping. For example, the alkylamido compound group would represent an alkyl group attached to the parent group through a starch group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent group through an alkyl group.

When a group is set to be "null," that means that group is missing. A "null" group that occurs between two other groups may also be understood to be collapsed or flanked. For example, if at - (CH2) SG1G2G3, element G2 is zero, then that group would become - (CH2) sGlG3.

The term "optionally substituted" means the foregoing group may be substituted or unsubstituted. When substituted, substituents on an "optionally substituted" group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated group of groups alone or in combination: lower alkyl, lower alkenyl, lower alkynyl lower, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkyl, lower perhaloalkyl, lower perhaloalkoxy, cycloalkyl, phenyl, aryl, lower haloalkoxy, lower acyloxy, lower carbonyl ox lower alkylcarbonyl carboxyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, alkylamino hydroxy, amino, lower arylamino, starch, nitro, thiolate, lower alkylthio, haloalkylthio, perhaloalkylthio, arylthio, sulfonate, sulfonic acid trisubstituted silyl, N 3, SH, SCH 3, C (O) CH 3, CO 2 CH 3, CO 2 H, pyridinyl, t iofen, furanyl, lower carbamate, and lower urea. Two substituents may be joined together to form five, six, or seven fused heterocyclic or carbocyclic rings fused to or consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy. An optionally substituted group may be unsubstituted (e.g. -CH2CH3), fully substituted (e.g.-CF2CF3), monosubstituted (e.g. -CH2CH2F) or level substituted anywhere between fully substituted and monosubstituted (e.g. -CH2CH2F). CH 2 CF 3). Where substitutes are reported without qualification regarding substitution, substituted and unsubstituted forms are covered. Where a substituent is qualified as "substituted," the substituted form is specifically intended. Additionally, different sets of optional substituents on a particular moiety may be defined as required; In these cases, the optional substitution will be as defined, often immediately after the phrase, "optionally substituted with"

The term R or the term R1, which appears by itself and without a number designation, unless otherwise defined, refers to a selected part of the group consisting of hydrogen, hydroxyl, halogen, alkyl, cycloalkyl, heteroalkyl aryl, heteroaryl and heterocycloalkyl, which may optionally be substituted. Such groups of R and R 'must be understood to be optionally substituted as defined herein. Whether a group of R has a number designation or not, each group of R, including R, R and Rn where η = (1, 2, 3, ... η), each substituent, and each term must be understood to be independently of each other in terms of selecting a group. If the entire variable, substitute, or term (eg, aryl, heterocycle, R, etc.) occurs more than once in a formula or generic structure, its definition at each occurrence is independent of the definition at each other occurrence. Those skilled in the art will recognize that certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written. Thus, as an example only, an asymmetric group such as - C (O) N (R) - can be joined to related clusters in carbon or nitrogen.

Asymmetric centers exist in the compounds of the present invention. These centers are designated by the symbols "R" or "S," depending on the configuration of the substituents around the chiral carbon atom. It is to be understood that the invention encompasses all steric isomeric forms including diastereomeric, enantiomeric and epimeric forms including as well as d-isomer and 1-isomer, and mixtures thereof. Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials containing chiral centers or by preparing mixtures of enantiomeric products followed by separation, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques. direct separation of enantiomers on chiral chromatographic columns or any other appropriate method known in the art. The stereochemically particular starting compounds are commercially available or may be made and resolved by techniques known in the art. Additionally, the compounds of the present invention may exist as geometric isomers. The present invention includes any useful isomer, trans, sin, anti, entgegen (e), and zusammen (Z), as well as appropriate mixtures thereof. Additionally, the compounds may exist as tautomers, including keto-enol tautomers; All tautomeric isomers are provided by this invention. As an example, the following pairs of tautomers illustrate how both forms are contemplated herein. In addition, the compounds of the present invention may exist unsolvated as well as solvated with pharmaceutically acceptable solvents. such as water, ethanol, and the like. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the present invention.

The term "bond" refers to a covalent bond between two atoms or two groups when the atoms joined by the bond are considered to be part of the larger substructure. A bond may be single, double or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.

The term "disease" as used herein is intended to be generally synonymous, and is used interchangeably with the terms "disorder" and "condition" (as in the medical condition), wherein such a reflection of an abnormal condition of the body or part of it. which impairs normal functioning and is typically manifested by distinguishable signs and symptoms.

The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as within a single capsule having a fixed ratio of active ingredients or in separate multiple capsules for each active ingredient. Further, such administration also encompasses the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

PDE4 "inhibitor"; is used herein to refer to a compound exhibiting an IC50 with respect to PDE4 activity of no more than about 100 μΜ and more typically no more than about 50μΜ, as measured in the PDE4 assay generally described herein. below. "IC50" is that inhibitor concentration which reduces the activity of an enzyme (e.g. PDE4) to half of the maximum level. Certain representative compounds of the present invention have been discovered to exhibit inhibition against PDE4. In certain embodiments, the compounds will exhibit an IC50 with respect to PDE4 no more than about 10 μΜ; in further embodiments, the compounds will exhibit an IC50 with respect to PDE4 no more than about 5 μΜ; however in further embodiments, compounds will exhibit an IC50 with respect to PDE4 of no more than approximately 1 μ, as measured in the PDE4 assay described herein. However, further embodiments, compounds will exhibit an IC50 with respect to PDE4 of no more than approximately 200 nM.

The phrase "therapeutically effective" is intended to describe the amount of active ingredients used in the treatment of a disease or disorder. This amount will achieve the objective of reducing or eliminating said disease or disorder.

As used herein, referring to the "treatment" of a patient is intended to include prophylaxis. The term "patient" means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, the patient is a human being.

The term "prodrug" refers to a compound that is made more active in vivo. Some of the present compounds may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Forehead, Bernard and Mayer, Joachim M. Wiley-VHCA7 Zurich, Switzerland 2003). The prodrugs of the compounds described herein are in the modified structural form of the compound which readily undergo chemical changes under physiological circumstances to provide the compound. Additionally, prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can slowly be converted to a compound when placed in a transdermal patch reservoir with an appropriate enzyme or chemical reagent. Prodrugs are often in some situations, may be easier to administer than the compound, or useful parent drug because, for example, they may be bioavailable by oral administration as the parent drug is not. The prodrug may also have its solubility improved in parenteral drug pharmaceutical compositions. A wide variety of prodrug derivatives are known in the art, such as those that depend on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound that was administered as an ester ("prodrug"), but otherwise metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound. The term "therapeutically acceptable prodrug" refers to those prodrugs or zwitterions that are suitable for use in contact with patients' tissues without improper toxicity, irritation and allergic response, are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use.

The compounds of the present invention may exist as therapeutically acceptable salts. The present invention includes the compounds listed above in the form of salts, including acid addition salts. Suitable salts include those formed with organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of pharmaceutically unacceptable salts may be of use in the preparation and purification of the compound in question. The basic addition salts may also be formed and pharmaceutically acceptable. For a more complete examination of salt preparation and selection, pharmaceutical salts refer to: Pharmaceutical Salts: Properties, Selection and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

The term "therapeutically acceptable salt" as used herein represents zwitterionic salts or forms of the compounds of the present invention that are water or oil soluble or dispersed and therapeutically acceptable as defined herein. Salts may be prepared during the final isolation and purification of the compounds or separated by reacting the appropriate compound as free base with an appropriate acid. Representative salts of the acid addition include acetate, adipose, alginate, L-ascorbate, aspartate, benzoate, benzenessulfonate (besylate), bisulfate, butyrate, camphorate, camforsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate , hemisulfate, heptanoate, hexanoate, hypurate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate 2 (isethionate), lactate, maleate, malonate, DL-mandelate, mesithylenesulfonate, naphthylenesulfonate, nicotinate, naphthalate sulfonate, phaephenate, phexalate Phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate (p-tosylate), and undecanoate. Also, the basic groups in the compounds of the present invention may be quaternized with methyl, ethyl, propyl and butyl, bromides and iodides; dimethyl, diethyl, dibutyl sulfates, and diamyl sulfates; decyl, lauryl, myristyl and sterile chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which may be employed to therapeutically acceptable acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric and organic acids such as oxalic, maleic, succinic, and citric. Salts may also be formed by coordinating the compounds with an alkaline earth or alkaline ion. However, the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.

Basic addition salts may be prepared during the final isolation and purification of the compounds by reacting a carboxyl group with an appropriate base such as hydroxide, carbonate or bicarbonate of a metal cation or with ammonia or a primary organic amine, secondary, or tertiary o. Therapeutically acceptable salt cations include lithium, sodium, potassium, calcium, magnesium and aluminum, as well as non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine diethylamine, ethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N, N-dibenzylphenethylamine, 1 epenamine, and N, N 1 dibenzylethylenediamine. Other representative organic amines useful for the formation of basic addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine and piperazine.

While it may be possible for the compounds of the present invention to be administered as the crude chemical, it is also possible to present them as a pharmaceutical formulation. Accordingly, provided herein are pharmaceutical formulations comprising one or more of certain compounds of the present invention or one or more pharmaceutically acceptable salts, esters, prodrugs, starches or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more. plus other therapeutic ingredients. The carriers should be "acceptable" in the sense that they are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Some of the known techniques, vehicles and excipients may be used as appropriate and as understood in the art; for example, in Remington Phamaceutical Sciences. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, for example by conventional mixing, dissolving, granulating, dredging, levigating, emulsifying, encapsulating, retaining or compressing processes.

Formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical use although the most appropriate route may depend on, for example, condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by some of the methods known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound of the present invention or a pharmaceutically acceptable salt, ester, starch, prodrug or solvate thereof ("active ingredient") with the carrier which constitutes one or more more accessory ingredient. Generally, the formulations are prepared by uniformly and intimately conducted by associating the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, forming the product within the desired formulation.

Formulations of the present invention suitable for oral administration may be presented as discrete units, such as capsules, sache or tablets, each containing a predetermined amount of the active ingredient; as a powder or granule; as a solution or suspension in an aqueous liquid or non-aqueous liquid or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

Pharmaceutical preparations which may be used orally include tablets, capsules made of gelatin as well as soft, closed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The tablets may be made by compression or molding, optionally with one or more accessory ingredients. The compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free form such as a powder or granule, optionally mixed with pastes, inert or lubricating diluents, active agents or surface dispersants. Molded tablets may be made by molding in a suitable machine a mixture of the spray compound moistened with an inert liquid diluent. The tablets may optionally be coated or labeled and may be formulated to provide slow or controlled release of the active ingredient. All formulations for oral administration should be in the appropriate dosages for such administration. Capsules may contain the active ingredients in the filler addition such as lactose, pastes such as starches and / or lubricants such as talc or stearate and optionally magnesium stabilizers. In soft capsules, the active compounds may be dissolved or suspended in appropriate liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are supplied with the appropriate coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol dioxide, and / or titanium, lacquer solutions, and mixtures. appropriate organic solvent or solvents. The dyes or pigments may be added to the tablets or dragee coatings for the identification or characterization of different active compound dose combinations.

The compounds may be formulated for parenteral administration by injection, for example by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, for example, ampoules or in multi-dose containers with an added condom. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The formulations may be presented in unit dosage form or in multi-dose containers, for example, closed ampoules and vials and may be stored in powder form or in a lyophilized (lyophilized) condition requiring only the addition of free water. sterile saline or sterile liquid pyrogen in the carrier, for example, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the type previously described.

Formulations for parenteral administration include aqueous and non-aqueous sterile (oily) solutions for injection of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the intended recipient's blood; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters such as ethyl or triglyceride oleate or liposome. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain appropriate stabilizers or agents that increase the solubility of the compounds to enable the preparation of highly concentrated solutions.

In addition, for the previously described formulations, the compounds may also be formulated as a depot preparation. Such long active formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with materials (e.g., as an emulsion in an acceptable oil) or appropriate ion exchange polymeric or hydrophobic resins, or as sparingly soluble derivatives, for example as a sparingly soluble salt.

For oral or sublingual administration, the compositions may take the form of tablets, lotions, lozenges, or gels formulated in the conventional manner. Such compositions may comprise the active ingredient on a flavoring basis, such as saccharin and acacia or tragacanth.

The compounds may also be formulated in rectal compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter, polyethylene glycol or other glycerides.

Certain compounds of the present invention may be administered topically, which is by non-systemic administration. This includes applying a compound of the present invention externally to the epidermis or oral cavity and instilling such a compound into the ear, eye and nose such that the compound does not significantly enter blood flow. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and

intramuscular.

Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation, such as gels, pomodas, lotions, creams, ointments or pastes, and eye drops suitable for administration to the eye. , to the ear or nose. The active ingredient for topical administration may comprise, for example, from 0.001% to 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w / w. In other embodiments, it may comprise less than 5% w / w. In certain embodiments, the active ingredient may comprise from 2% w / w to 5% w / w. In other embodiments, it may comprise from 0.1% to 1% w / w of the formulation.

Gels for topical or transdermal administration may generally comprise a mixture of volatile solvents, non-volatile solvents and water. In certain embodiments, the volatile solvent component of the buffered solvent system may include lower alkyl (C1-C6) alcohols, lower alkyl glycols and lower glycol polymers. In additional embodiments, the volatile solvent is ethanol. The volatile solvent component is considered to act as a penetration enhancer, while also producing a cooling effect on the skin as it evaporates. The nonvolatile solvent portion of the buffered solvent system is selected from lower alkylene glycols and lower glycol polymers. In certain embodiments, propylene glycol is used. The nonvolatile solvent slows volatile solvent evaporation and reduces the vapor pressure of the buffered solvent system. The amount of this non-volatile solvent component, as with the volatile solvent, is determined by the compound or pharmaceutical drug being used. When too little of the nonvolatile solvent is in the system, the pharmaceutical compound may crystallize due to evaporation of the volatile solvent, while an excess may result in a lack of bioavailability to poor drug release from the solvent mixture. The buffer component of the buffered solvent system may be selected from any buffer commonly used in the art; In certain embodiments water is used. A common ratio of ingredients is approximately 20% nonvolatile solvent, approximately 40% volatile solvent and approximately 40% water. There are several optional ingredients that can be added to the topical composition. These include, but are not limited to, cheeses and gelling agents. Suitable gelling agents may include, but are not limited to, semi-synthetic cellulose derivatives (such as hydroxypropyl methylcellulose) and synthetic polymers, and cosmetic agents.

Lotions include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of the drops. The lotions or

Skin-applying liniments may also include an agent for accelerating drying and cooling the skin, such as an alcohol or an acetone, and / or a humectant such as glycerol or an oil such as castor oil or peanut oil.

Creams, ointments or pastes are semi-solid formulations of the active ingredient for external application. They can be made by mixing the active ingredient in finely divided or pulverized form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a grease or non-grease base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, peanut, castor or olive; wool fat or its derivatives or a fatty acid such as stearic or oleic acid together with an alcohol such as propylene glycol or a macrogel. The formulation may incorporate any surface active agent such as an anionic, cationic or nonionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silica silicas and other ingredients such as lanolin may also be included.

Drops may comprise aqueous or oily sterile solutions or suspensions and may be prepared by dissolving the active ingredient in an appropriate aqueous solution of a bactericidal and / or fungicidal agent and / or any other suitable preservative and, in certain embodiments, including an active agent of surface. The resulting solution can then be lightened by filtration, transferred to an appropriate container which is then sealed and autoclaved or held at 98-100 ° C for half an hour. Alternatively, the solution can be sterilized by filtration and transferred to the container by aseptic technique. Examples of suitable bactericidal and fungicidal agents for inclusion in the droplets are nitrate or phenylmercuric acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for preparing an oily solution include glycerol, dilute alcohol and propylene glycol.

Formulations for topical administration in the mouth, for example, buccally or sublingually, include lozenges comprising the active ingredient in a flavored base such as saccharin and acacia or tragacanth, and lozenges comprising the active ingredient in a base such as gelatin and glycerin or saccharin and acacia.

For administration by inhalation, the compounds may conveniently be released from an insufflator, pressurized nebulizer packs or other convenient means of releasing an aerosol spray. Pressurized packages may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane,

dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to release a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mixture of the compound and an appropriate powder base such as lactose or starch. The powder composition may be presented in unit dosage form in, for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.

Preferred unit dosage formulations are those containing an effective dose, as reported below, or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients mentioned particularly above, the formulations described above may include other conventional agents in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

The compounds may be administered orally or by injection at a dose of 0.1 to 500 mg / kg per day. The dose range for adult humans is usually 5mg to 2g / day. Tablets or other forms provided in discrete units may conveniently contain an amount of one or more compounds that are effective in such dosage or as multiples thereof, for example units containing 5mg to 50mg, usually around 10mg to 200mg. .

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

The compounds may be administered in various embodiments, for example orally, topically or by injection. The precise amount of compound administered to a patient will be the responsibility of the attending physician. The specific dose level for any particular patient will depend on a variety of factors including activity of the specific compound employed, age, body weight, general health, gender, diets, administration time, route of administration. , excretion rate, drug combination, disorder needs to be treated, and severity of indication or condition being treated. Also, the route of administration may vary depending on the condition and its severity.

In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient receiving one of the compounds therein is hypertension, then it may be appropriate to administer an antihypertensive agent in combination with the initial therapeutic agent. Or, as an example only, the therapeutic efficacy of one of the compounds described herein may be enhanced by the administration of an adjuvant (ie, the adjuvant alone may have only minimal therapeutic benefit, but in combination with another therapeutic agent, the therapeutic benefit). total to the patient is highlighted). Or, as an example only, the benefit experienced by a patient may be increased by administering one of the compounds described therein with another therapeutic agent (which also includes a therapeutic regimen) which also has the therapeutic benefit. By way of example only, in a treatment for diabetes involving the administration of one of the compounds described herein, the increased therapeutic benefit may also result in providing the patient with another therapeutic agent for diabetes. In any case, regardless of the disease, disorder or condition being treated, the total benefit experienced by the patient may simply be additive to both therapeutic agents or the patient may experience a synergistic benefit.

In any case, multiple therapeutic agents (at least one of which is a compound of the present invention) may be administered in any order or even simultaneously. If simultaneously, multiple therapeutic agents may be provided in a single unified form, or in multiple forms (as an example only, or as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, synchronization between multiple doses can be of any length of time ranging from a few minutes to four weeks.

Thus, in another aspect, the present invention provides methods for treating PDE4-mediated disorders in a human or animal subject in need of such treatment which comprises administering to said subject an amount of a current compound of the invention effective in reducing or preventing said subject. disorder in the subject in combination with at least one additional agent for treating said disorder which is known in the art. In a related aspect, the present invention provides therapeutic compositions comprising at least one compound of the present invention in combination with one or more additional agents for the treatment of PDE4-mediated disorders. The compounds of the present invention may be useful in treating PDE4-mediated disease, disorders and conditions. In certain embodiments, said compounds may find use in treating acute and chronic pain and inflammation. The compounds of the present invention may be useful for treating patients with neuropathy, neuropathic pain, or inflammatory pain such as reflex sympathetic dystrophy / causalgia (nerve injury), peripheral neuropathy (including diabetic neuropathy), intractable cancer pain, of complex regional pain and retention neuropathy (carpel tunnel syndrome). The compounds may also be useful in the treatment of pain associated with acute herpes (herpes zoster), posterpetic neuralgia (PHN) and associated pain syndromes such as eye pain. The compounds may further be useful as analgesics in the treatment of pain such as surgical analgesia, or as an antipyretic for the treatment of fever. Indications for pain include, but are not limited to, post-surgical pain for various surgical procedures including post-cardiac surgery, dental pain / extraction, pain resulting from cancer, muscle pain, breast pain, pain resulting from skin injury, pain. in the back, headaches of various etiologies, including migraine, and the like. The compounds may also be useful for the treatment of pain-related disorders such as tactile allodynia and hyperalgesia. The pain may be somatogenic (or nociceptive or neuropathic), acute and / or chronic. PDE4 inhibitors of the present invention may also be useful under conditions where fentanyl NSAIDs, morphine or opiates and / or other opioid analgesics would be traditionally administered.

In addition, the compounds of the present invention may be used in the treatment or prevention of opioid tolerance in patients requiring delayed opioid analgesics, benzodiazepine tolerance in patients taking benzodiazepines, and other addiction behavior, for example nicotine addiction. , alcoholism and eating disorders. In addition, the compounds and methods of the present invention may be useful in treating or preventing drug withdrawal symptoms, for example treating or preventing symptoms of opioid withdrawal, alcohol, or tobacco addiction.

In addition, the compounds of the present invention may be used to treat insulin resistance and other metabolic disorders such as atherosclerosis that are typically associated with exaggerated inflammatory signaling.

The present invention encompasses therapeutic methods using novel selective PDE4 inhibitors to treat or prevent respiratory disease or condition, including medical therapeutic methods for preventing and treating a respiratory disease or condition including: asthmatic conditions including allergen-induced asthma, induced asthma by exercise, pollution-induced asthma, cold-induced asthma, and virus-induced asthma; asthma-related diseases such as airway hyperreactivity and minor airway disease; chronic obstructive pulmonary diseases that include chronic bronchitis with normal airflow, chronic bronchitis with airway obstruction (chronic obstructive bronchitis), emphysema, asthmatic bronchitis, and bullous disease; and other lung diseases involving inflammation including bronchitis, bronchioectase, cystic fibrosis, pigeon disease, farmer's lung, acute respiratory distress syndrome, pneumonia, pneumonitis, aspiration or inhalation injury, fat embolism of the lung, acute pulmonary edema, acute mountain sickness, acute pulmonary hypertension, persistent pulmonary hypertension of newborn syndrome, perinatal aspiration, hyaline membrane disease, acute pulmonary thromboembolism, heparin-protamine reactions, sepsis, status asthamticus, hypoxia, dyspnea, hypercapnea, hyperinflation, hypoxemia and cough. In addition, the compounds disclosed herein would find use in the treatment of allergic disorders such as delayed type hypersensitivity reaction, allergic contact dermatitis, allergic rhinitis.

and chronic sinusitis.

Other disorders or conditions that may be treated by the compounds of the present invention include inflammation and related disorders. The compounds of the present invention may be useful as anti-inflammatory agents with the added benefit of having significantly less harmful side effects. The compounds may be useful for treating arthritis including, but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis, acute rheumatic arthritis, enteropathic arthritis, psoriatic arthritis, reactive arthritis (Reiter's syndrome), and pyogenic arthritis, and autoimmune diseases, including systemic lupus erythematosus, hemolytic syndromes, autoimmune hepatitis, autoimmune neuropathy, vitiligo (autoimmune thyroiditis), anemias, myositis including polymyositis, alopecia greata, syndrome Goodpasture, hypofitis, and pulmonary fibrosis.

The compounds may also be useful for treating osteoporosis and other bone related disorders.

These compounds may also be used to treat gastrointestinal conditions such as reflux esophagitis, diarrhea, inflamed bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, Graves' disease (hyperthyroidism), necrotizing enterocolitis and ulcerative colitis. The compounds may also be used in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis.

In addition, the compounds of the invention may also be useful in organ or single transplant patients or in combination with conventional immunomodulators. Examples of conditions to be treated in such patients include graft versus host reaction (i.e. graft versus host disease), allograft rejections (e.g., acute allograft rejection and chronic allograft rejection), transplant reperfusion injury, and early rejection. transplantation (eg acute allograft rejection).

Still further, the compounds of the invention may be useful in the treatment of pruritis and vitiligo.

The compounds of the present invention may also be useful in treating tissue damage in diseases such as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction including miastemia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephritis, nephrotic syndrome, Langerhans cell histiocytosis, glomerulonephritis, reperfusion injury, pancreatitis, interstitial cystitis, Behcet syndrome, polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, ischemia including myocardial ischemia, cardiovascular ischemia and ischemia secondary to cardiac arrest, cirrhosis, septic shock, endotoxic shock, gran negative sepsis, toxic shock syndrome, heart attack, ischemia reperfusion injury, multiple organs, restenosis that includes r stenosis following coronary bypass surgery, and the like. The compounds of the present invention may also be useful for the treatment of certain nervous system disorders and disorders. Central nervous system disorders in which PDE4 inhibition may be useful include cortical dementias including Alzheimer's disease and mild cognitive impairment (MCI), central nervous system damage resulting from heart attack, ischemia including cerebral ischemia (both ischemia focal thrombotic attack such as global ischemia (eg secondary to cardiac arrest) and trauma Neurodegenerative disorders in which PDE4 inhibition may be useful include nerve degeneration or nerve necrosis in disorders such as hypoxia, hypoglycemia, epilepsy and in cases of central nervous system (CNS) trauma (such as spinal cord and head injury), seizures and hyperbaric oxygen toxicity, dementia, for example, presenile dementia and AIDS-related dementia, cachexia, Sydenham's chorea, Huntington's disease, Parkinson's disease, Amyotrophic lateral sclerosis (ALS), Korsakoff syndrome and imbecility in relation to a disorder Additional disorders in which PDE4 inhibition may prove useful include central and peripheral nervous system neuropathies (including, for example, IgA neuropathy, membranous neuropathy and idiopathic neuropathy), chronic inflammatory demyelinating polyneuropathy, transverse myelitis, Gullain-Barre disease, encephalitis and cancers of the nervous system. CNS function disorders in which PDE4 inhibitors may find use include sleep disorders, schizophrenia, depression, depression or other symptoms associated with Premenstrual Syndrome (PMS), and anxiety.

In addition, the compounds of the present invention may also be useful in inhibiting PDE4 activity for ameliorating systemic disorders including systemic hypotension associated with septic and / or toxic hemorrhagic shock induced by a wide variety of agents; as a therapy with cytokines such as TNF, IL-I and IL-2; and as an adjunct to short term immunosuppression in transplant therapy.

Still other disorders or conditions that may be

Treated by the compounds of the present invention include the prevention or treatment of cancer, such as colorectal cancer, and breast, lung, prostate, bladder, cervix, and skin cancer. The compounds of the invention may be used in the treatment and prevention of malignancies including, but not limited to, brain cancer, bone cancer, leukemia, lymphoma, epithelial cell-derived neoplasia (epithelial carcinoma), such as cell carcinoma basal, adenocarcinoma, gastrointestinal cancer, such as lip cancer, mouth cancer, esophageal cancer, small intestine cancer and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cancer cervical cancer, lung cancer, breast cancer, and skin cancer, such as squamous and basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that affect epithelial cells throughout the body. The neoplasm can be selected from gastrointestinal cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, lung cancer, breast and skin cancer, such as squamous cell and cell cancer. basal. The compounds and methods of the present may also be used to treat fibrosis that occurs with radiation therapy. The compounds and methods of the present can be used to treat subjects who have adenomatous polyps, including those with familial adenomatous polyposis (FAP). Additionally, the present compounds and methods may be used to prevent polyps from forming in patients at risk of PAF. The compounds of the present invention may be used in the treatment of ophthalmic diseases such as dry eye, glaucoma, corneal neovascularization, optic neuritis, Sjogren's syndrome, retinal ganglion degeneration, ocular ischemia, retinitis, retinopathies, uveitis, ocular photophobia and inflammation. and pain associated with acute injury to eye tissue. Specifically, the compounds may be used to treat glaucomatous retinopathy and / or diabetic retinopathy. The compounds may also be used to treat inflammation or postoperative pain such as ophthalmic surgery such as cataract surgery and refractive surgery.

In addition, the compounds of the present invention may be used in the treatment of menstrual cramps, dysmenorrhea, premature birth, endometriosis, tendonitis, bursitis, skin related conditions such as psoriasis, eczema, burns, sunburn, dermatitis, pancreatitis, hepatitis, lichen planus, scleritis, scleroderma, dermatomyositis and the like. Other conditions in which the compounds of the present invention may be used include diabetes (type I or type II), atherosclerosis, congestive heart failure, myocarditis, atherosclerosis, cerebral ischemia, angiogenesis, pulmonary hypertension, and aortic aneurysm.

The present compounds may also be used in co-therapies, partially or completely, in place of other conventional anti-inflammatory therapies, such as in conjunction with steroids, NSAIDs, selective COX-2 inhibitors, 5-lipoxygenase inhibitors, LTB4 antagonists and inhibitors. of hydrolase LTA4. The compounds of the present invention may also be used to prevent tissue damage when combined therapeutically with antibacterial or antiviral agents.

In addition to being useful for human treatment, the compounds and formulations of the present invention are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents and the like. Most preferred animals include horses, dogs and cats.

GENERAL SYNTHETIC METHODS FOR PREPARING COMPOUNDS

The following schemes practice the present invention.

<formula> formula see original document page 60 </formula>

<formula> formula see original document page 60 </formula>.

Scheme 3

<formula> formula see original document page 60 </formula> When R contains an ester: <formula> formula see original document page 61 </formula> When R101 contains a bromide:

<formula> formula see original document page 61 </formula> invention is further illustrated by the following

EXAMPLE 1

8- (Cyclopentyloxy) -4- (3,5-dichloropyridin-4-ylamino) -7-methoxyquinolin-2 (1H) -one

<formula> formula see original document page 61 </formula> Step 1

Sulfuric acid (3.0 µL, 56 mmol) was added dropwise over 2 minutes to a solution of methyl 3-hydroxy-4-methoxybenzoate (3.64 g, 20 mmol), tetrabutylammonium hydrogen sulfate (340 mg, 1 mL). 0.1 mmol), isopropyl nitrate (5.0 mL, 50 mmol), and dichloromethane (40 mL) at 0 ° C. The reaction was allowed to warm to room temperature, maintained for 45 min., And then quenched with ice water (100 mL). This mixture was extracted with dichloromethane (250 mL χ 2). The combined extracts were dried, filtered, concentrated, and purified by silica gel chromatography (4: 1 → 3: 7; hexanes: ethyl acetate) to afford methyl 3-hydroxy-4-methoxy-2-nitrobenzoate. : MS (ESI): 228.4.

Step 2

A mixture of methyl 3-hydroxy-4-methoxy-2-nitrobenzoate (1.14 g, 5.0 mmol), bromocyclopentane (0.7 mL, 6.5 mmol), potassium carbonate (2.0 g, 14 mmol ), and anhydrous acetonitrile (15 mL) was refluxed under N 2. After 19 h, the reaction was allowed to cool to room temperature, concentrated, and purified by silica gel chromatography (4: 1- + 3: 2; hexanes: ethyl acetate) to provide 3- (cyclopentyloxy) -4-methoxy. Methyl nitrobenzoate: MS (ESI): 296.5.

Step 3

A mixture of methyl 3- (cyclopentyloxy) -4-methoxy-2-nitrobenzoate (750 mg, 2.54 mmol), 10% Pd / C (50% H2O, 500 mg, 0.23 mmol Pd), and Methanol (10 mL) was stirred vigorously at room temperature under an atmosphere of H2. After 21 h, the mixture was filtered through Celite and concentrated to afford methyl 2-amino-3- (cyclopentyloxy) -4-methoxybenzoate: MS (ESI): 266.5.

Step 4

A solution of methyl 2-amino-3- (cyclopentyloxy) -4-methoxybenzoate (5.54 g, 20.9 mmol), acetic anhydride (21.0 mL, 222 mmol), and dioxane (35 mL) was heated at 40 ° C under N 2 for 17 h and then allowed to cool to room temperature. Water (10 mL) was added, and after 15 min. Stirring, the reaction was concentrated to afford methyl 2-acetamido-3- (cyclopentyloxy) -4-methoxybenzoate: MS (ESI): 307.9.

Step 5

A solution of methyl 2-acetamido-3- (cyclopentyloxy) -4-methoxybenzoate (6.42 g, 20.9 mmol) and anhydrous THF (60 mL) was added via syringe pump (1 mL / min) to a solution of KHMDS (150 mL, 0.5M PhMe, 75 mmol) at -78 ° C under N 2. The reaction was allowed to slowly warm to room temperature while the bath expired overnight. After 17 h, the reaction was poured into ice / water (250 mL), allowed to stir for 10 min, and the layers separated. The aqueous reaction was washed with ether (150 mL), acidified with concentrated HCl (7 mL), and filtered to afford 8- (cyclopentyloxy) -4-hydroxy-7-methoxyquinolin-2 (1H) -one: MS (ESI ): 276.0.

Step 6

A mixture of 8- (cyclopentyloxy) -4-hydroxy-7-methoxyquinolin-2 (1H) -one (350 mg, 1.3 mmol), ammonium acetate (4.0 g, 52 mmol), and m-xylene Anhydrous salt (10 mL) was heated to 150 ° C under N 2 for 48 h and then allowed to cool to room temperature. The mixture was concentrated to dryness, diluted with water (25 mL), stirred for 2 min, sonicated for 1 min, and then stirred for 5 min. The free-flowing solid was filtered, washed with water (25 mL), and pumped dry to afford 4-amino-8- (cyclopentyloxy) -7-methoxyquinolin-2 (1H) -one: MS (ESI): 274.9.

Step 7

.4-Amino-8- (cyclopentyloxy) -7-methoxyquinolin-2 (1H) -one (340 mg, 1.24 mmol) was added in 3 portions over 5 min. to a mixture of sodium hydride (110 mg, 60%, 2.75 mmol) and DMSO (4 mL) at room temperature under N 2. After 5 min. 3,4,5-trichloropyridine (271 mg, 1.49 mmol) was added. After 19 h, more sodium hydride (100 mg, 60%, 2.5 mmol) was added followed by an additional 3,4,5-trichloropyridine (250 mg, 1.37 mmol). After an additional 4h, the reaction was poured into IM KH2PO4 (75 mL) and stirred for 5 min. The solids were filtered, washed with water (25 mL), and then purified on reverse phase HPLC (3: 7-1: 0; acetonitrile: water). In some cases further purification by silica gel chromatography (1: 0 ^ 9: 1; dichloromethane: methanol) was required to provide 8- (cyclopentyloxy) -4- (3,5-dichloropyridin-4-ylamino) -7 -methoxyquinolin-2 (1H) -one: 1 H NMR (400 MHz, DMSO-d 6): δ 9.39 (s, 1Η), 8.86 (s, 1H), 8.76 (s, 2H), 7.87 (d, 1H), 7.06 (d, 1H), 4.97 (m, 1H), 4.78 (s, 1H), 3.90 (s, 3H), 1.83-1.48 (m, 8H); MS (ESI): 419.7.

EXAMPLE 2

.8- (Cyclopentyloxy) -4- (3,5-dichloropyridin-4-yloxy) -7-methoxyquinolin-2 (IH) -one <formula> formula see original document page 64 </formula>

The title compound was isolated from the purification of Example 1, step 7. 1H NMR (400 MHz, DMSO-d6): δ 10.28 (s, 1H), 8.84 (s, 2H), 7.71 (d, 1H), 7.11 ( d, 1H), 5.35 (s, 1H), 4.97 (m, 1H), 3.91 (s, 3H), 1.86-1.43 (m, 8H); MS (ESI): 420.7.

EXAMPLE 3

.8- (Cyclopropylmethoxy) -4- (3,5-dichloropyridin-4-ylamino) -7-methoxyquinolin-2 (1H) -one <formula> formula see original document page 64 </formula>

The title compound was prepared from methyl 3-hydroxy-4-methoxy-2-nitrobenzoate (Example 1, step 1) and (bromomethyl) cyclopropane following the procedures outlined in Example 1. 1H NMR (400 MHz, DMSO-ds) : δ 9.91 (s, 1H), 8.83 (s, 1H), 8.76 (s, 2H), 7.87 (d, 1H), 7.03 (d, 1H), 4.78 (s, 1H), 3.89 (s, 3H) 3.84 (d, 2H), 1.27 (τη, 1H), 0.45 (m, 2H), 0.25 (m, 2H); MS (ESI): 405.8.

EXAMPLE 4

.8- (Cyclopentyloxy) -4- (3,5-dichloropyridin-4-ylamino-7-methoxy-1-methylquinolin-2 (1H) -one <formula> formula see original document page 65 </formula> Step 1

A solution of methyl 2-acetamido-3- (cyclopentyloxy) -4-methoxybenzoate (1.6 g, 5.2 mmol, Example 1, step 4) and anhydrous THF (30 mL) was added over 5 min. to a mixture of sodium hydride (230 mg, 5.75 mmol) and anhydrous THF (10 mL) at 0 ° C under N 2. The reaction was allowed to warm to room temperature and after 20 min cooled back to 0 ° C. A solution of iodomethane (1.06 g, 0.0075 mol) and anhydrous THF (10 mL) was added over 3 min. The reaction was allowed to warm to room temperature and after 30 min. , concentrated. The residue was diluted with ethyl acetate (40 mL) and washed with brine (10 mL χ 2). The organic layer was dried, filtered, and concentrated to afford methyl 3- (cyclopentyloxy) -4-methoxy-2- (N-methylacetamido) benzoate: MS (ESI): 322.1.

Step 2

The title compound was prepared from 3-

(cyclopentyloxy) -4-methoxy-2- (N-methylacetamido) benzoate

methyl following the procedures outlined in Example 1. 1 H NMR (400 MHz, DMSO-d 6): δ 8.75 (s, 1H), 8.74 (s, 2H), 7.92 (d, 1H), 7.13 (d, 1H), 4.92 (s, 1H), 4.53 (m, 1H), 3.90 (s, 3H), 3.59 (s, 3H), 1.80-1.48 (m, 8H); MS (ESI): 433.9.

EXAMPLE 5

.8- (Cyclopentyloxy) -4- (3,5-dimethylpyridin-4-ylamino-7-methoxyquinolin-2 (IH) -one <formula> formula see original document page 66 </formula>

The title compound was prepared from 4-bromo-3,5-dimethylpyridine and 4-amino-8- (cyclopentyloxy) -7-

methoxyquinolin-2 (1H) -one (Example 1, step 6) following the procedure outlined in Example 8. 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.44 (s, 1H), 8.40 (s, 2H), 7.88 (d, 1H), 7.03 (d, 1H), 4.96 (m, 1H), 4.51 (s, 1H), 3.90 (s, 3H), 2.13 (s, 6H), 1.80- 1.54 (m, 8H); MS (ESI): 380.2.

EXAMPLE 6

1,3-Dibromo-8- (cyclopentyloxy) -4- (3,5-dichloropyridin-4-ylamino) -7-methoxyquinolin-2 (IH) -one <formula> formula see original document page 66 </formula>

N-Bromosuccinimide (0.118 g, 0.61 mmol) was added to a solution of 4- (3,5-dichloropyridin-4-ylamino) -8- (cyclopentyloxy) -7-methoxyquinolin-2 (1H) -one (0.100 g, 0.240 mmol, Example 1) and anhydrous DMF (2 mL) at 0 ° C. After 2 h at 0 ° C, the mixture was poured into water, and the precipitate was filtered to give 1,3-dibromo-8- (cyclopentyloxy) -4- (3,5-dichloropyridin-4-ylamino) -7-methoxyquinolin. -2 (1H) -one: 1 H NMR (400 MHz, DMSO-d 6): δ 10.5 (s, 1H), 8.59 (s, 2H), 6.76 (d, 1H), 6.61 (d, 1H), 4.87 ( m, 1H), 3.80 (s, 3H), 1.82-1.51 (m, 8H); MS (ESI): 575.8. EXAMPLE 7

.3-Bromo-8- (cyclopentyloxy) -4- (3,5-dichloropyridin-4-ylamino) -7-methoxyquinolin-2 (IH) -one <formula> formula see original document page 67 </formula> added to a solution of 4- (3,5-dichloropyridin-4-ylamino) -8- (cyclopentyloxy) -7-methoxyquinolin-2 (1H) -one (0.246 g, 0.585 mmol, Example 1) and anhydrous DMF (3 mL) at 0 ° C. After 4 h at 0 ° C, the mixture was poured into water, and the precipitate was filtered off. Saturated sodium thiosulfate solution (1 mL) was added to a filter cake and methanol solution (5 mL). After the dibromo intermediate was consumed by LCMS, the mixture was diluted with water and extracted with EtOAc. The organic extract was dried, filtered, and concentrated to afford 3-bromo-8- (cyclopentyloxy) -4- (3,5-dichloropyridin-4-ylamino) -7-methoxyquinolin-2 (1H) -one: 1 H NMR ( 400 MHz, DMSO-d 6): δ 10.56 (s, 1H), 8.88 (Br s, 1H), 8.42 (s, 2H), 7.62 (d, 1H), 7.04 (d, 1H), 4.98 (m, 1H ), 3.89 (s, 3H), 1.84-1.51 (m, 8H); MS (ESI): 497.8.

EXAMPLE 8

.8- (Cyclopropylmethoxy) -4- (3,5-dimethylpyridin-4-ylamino) -7-methoxyquinolin-2 (1H) -one <formula> formula see original document page 67 </formula> A 4-bromine solution -3,5-dimethylpyridine (1.16 g, 6.21 mmol) and degassed toluene (5 mL) was added to

N-Bromosuccinimide (0.104 g, 0.585 mmol) was

an

mixture

in

4-amino-8- (cyclopropylmethoxy) -7-methoxyquinolin-2 (1H) -one (1.94 g, 7.45 mmol, intermediate for Example 3), Pd2 (dba) 3, (0.28 g, 0.31 mmol), 2,2-dicyclohexylphosphorane triisopropylbiphenyl (0.59 g, 1.24 mmol), sodium tert-butoxide (1.20 g, 12.4 mmol), and degassed toluene (20 mL) under N 2 . The mixture was heated at 100 ° C for 2 h, allowed to cool to room temperature, sonicated until the solids broke, and then filtered through Celite with EtOAc (500 mL). The filtrate was concentrated, purified by silica gel chromatography (0-8% MeOH / CH 2 Cl 2), and then repurified by reverse phase HPLC (25-100% MeCN / H 2 O) to afford 8- (cyclopropyl methoxy) -4- (3,5-dimethylpyridin-4-

Ylamino) -7-methoxyquinolin-2 (1H) -one: 1 H NMR (400 MHz, DMSO-d 6): δ 9.64 (s, 1H), 8.43 (s, 1H), 8.42 (s, 2H), 7.89 (d , 1H), 7.03 (d, 1H), 4.54 (s, 1H), 3.91 (s, 3H), 3.85 (d, 2H), 2.15 (s, 6H), 1.28 (m, 1H), 0.47 (m, 2H) 0.28 (m, 2H); MS (ESI): 365.8.

methyl pyran-2-yloxy) ethyl) acetamido) benzoate was prepared from methyl 2-acetamido-3- (cyclopentyloxy) -4-methoxybenzoate (Example 1, step 4) following the procedure outlined in Example 4 (except: solvent was DMF; temperature was 33 ° C; time was night). MS ESI): 458.2 (M + Na).

EXAMPLE 9

.8- (Cyclopentyloxy) -4- (3,5-dichloropyridin-4-ylamino) -1- (2-hydroxyethyl) -7-methoxyquinolin-2 (1H) -one

<formula> formula see original document page 68 </formula>

Step 1

.3- (cyclopentyloxy) -4-methoxy-2- (N- (2- (tetrahydro-2H-

Step 2

.8- (Cyclopentyloxy) -4- (3,5-dichloropyridin-4-ylamino) -7-methoxy-1- (2- (tetrahydro-2H-pyran-2-one)

yloxy) ethyl) quinolin-2 (1H) -one was prepared from 3- (cyclopentyloxy) -4-methoxy-2- (N- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) acetamido) benzoate methyl following the procedures outlined in Example 1. (ESI): 570 (M + Na).

Step 3

P-Toluenesulfonic acid (172 mg, 1.0 mmol) was added to a solution of 8- (cyclopentyloxy) -4- (3,5-dichloropyridin-4-ylamino) -7-methoxy-1- (2- (tetrahydro) 2H-pyran-2-yloxy) ethyl) quinolin-2 (1H) -one (2.4 g, 4.4 mmol) and methanol (100 mL). After stirring overnight, the reaction was concentrated, diluted with dichloromethane (100 mL), and then washed with saturated NaHCO 3 (20 mL) followed by water (20 mL). The organic layer was dried, filtered, concentrated, and recrystallized from dichloromethane / petroleum ether (1: 2) to afford 8- (cyclopentyloxy) -4- (3,5-dichloropyridin-4-ylamino) -1- (2- (hydroxyethyl) -7-methoxyquinolin-2 (1H) -one: 1 H NMR (400 MHz, DMSO-d 6): δ 8.74 (s, 2H), 8.73 (s, 1H), 7.91 (d, 1H), 7.11 ( d, 1H), 4.92 (s, 1H), 4.65 (t, 2H), 4.59 (m, 1H), 4.50 (t, 1H), 3.90 (s, 3H), 3.32 (m 2H), 1.80-1.48 ( m, 8H) MS (ESI): 463.9.

EXAMPLE 10

.8- (Cyclopentyloxy) -4- (3,5-dichloropyridin-4-ylamino) -1- (2-dimethylamino) ethyl) -7-methoxyquinolin-2 (IH) -one <formula> formula see original document page 69 </formula>

Step 1

Dess-Martin Periodinane (933 mg, 2.2 mmol) was added to a solution of 8- (cyclopentyloxy) -4- (3,5-dichloropyridin-4-ylamino) -1- (2- (hydroxyethyl) -T-

methoxyquinolin-2 (1H) -one (500 mg, 1.08 mmol, example 9) and CH 2 Cl 2 (30 mL) at 0 ° C. After 30 min. , the mixture was allowed to warm to room temperature. When the starting material was consumed, the reaction was diluted with dichloromethane (25 mL), washed with aqueous NaOH (20 mL of χ 2), and then washed with water (20 mL). The organic layer was dried, filtered, concentrated, and purified by silica gel chromatography (1: 2 → 1: 1; ethyl acetate: petroleum ether) to afford 2- (8- (cyclopentyloxy) -4- (3,5-Dichloropyridin-4-ylamino) -7-methoxy-2-oxoquinolin-1 (2H) -yl) acetaldehyde: MS (ESI): 462.2.

Step 2

Titanium (IV) isopropoxide (496 mg, 1.74 mmol) and 2- (8- (cyclopentyloxy) -4- (3,5-dichloropyridin-4-ylamino) -7-methoxy-2-oxoquinolin-1 ( 2H) -yl) acetaldehyde (400 mg, 0.87 mmol) was added sequentially to a solution of dimethylamine hydrochloride (144 mg, 1.74 mmol), triethylamine (176 mg, 1.74 mmol), and absolute ethanol. (20 mL). After stirring overnight, sodium borohydride (50 mg, 1.3 mmol) was added. After an additional 3h, the reaction was poured into aqueous ammonia (30 mL) and then filtered-washed with dichloromethane. The filtrate was extracted with dichloromethane (50 mL of χ 3). The combined extracts were dried, filtered, concentrated, and purified by reverse phase HPLC to afford 8- (cyclopentyloxy) -4- (3,5-dichloropyridin-4-ylamino) -1,1- (2- (dimethylamino) ethyl) -7-methoxyquinolin-2 (1H) -one: 1H NMR (400 MHz, DMS0-d6): δ 8.75 (s, 1H), 8.73 (s, 2H), 7.91 (d, 1H), 7.12 (d, 1H), 4.94 (s, 1H), 4.71 (t, 2H), 4.58 (m, 1H), 3.90 (s, 3H), 2.22 (m, 2H), 2.04 (s, 6H), 1.80-1.50 ( m, 8H); MS (ESI): 491.0.

EXAMPLE 11

6- (4- (3,5-Dichloropyridin-4-ylamino) -7-

methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy) hexanoic Step 1

Concentrated HCl (15 mL) was added to a solution of 8- (cyclopropylmethoxy) -4- (3,5-dichloropyridin-4-ylamino) -7-methoxyquinolin-2 (1H) -one (1.2 g, 2, 90 mmol, example 3) and methanol (8 mL). The reaction mixture was heated at 50 ° C for 4h and then concentrated. The residue was neutralized with saturated NaHCO 3, filtered (washed with ethanol and ether), and dried to afford 4- (3,5-dichloropyridin-4-ylamino) -8-hydroxy-7-methoxyquinolin-2 (1H) -one: MS (ESI): 352.

Step 2

Sodium hydroxide (54 mg, 1.35 mmol) was added to a solution of 4- (3,5-dichloropyridin-4-ylamino) -8-hydroxy-7-methoxyquinolin-2 (1H) -one (380 mg 1.08 mmol) and DMSO (20 mL) at room temperature under N2. After 1h, ethyl 6-bromohexanoate (770 mg, 3.45 mmol) was added, and the mixture was heated at 30 ° C for 5h. The reaction was quenched with water droplets, poured into 0.5 M KH2PO4, and extracted with EtOAc (100 mL χ 3). The combined extracts were washed with water and then brine, dried, filtered, concentrated, and purified by silica gel chromatography (ethyl acetate: pet. Ether) to afford 6- (4- (3,5-dichloropyridin-4 - ethylamino) -7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy) ethyl hexanoate: MS (ESI): 494.0.

Step 3

Lithium hydroxide (2.0 mL, IM, 2.0 mmol) was added to a solution of 6- (4- (3,5-dichloropyridin-4-ylamino) -7-methoxy-2-oxo-1,2) ethyl dihydroquinolin-8-yloxy) hexanoate (100 mg, 0.20 mmol), MeOH (2 mL), and THF (8 mL). The mixture was stirred for 24h, quenched with IM HCl (30 mL), and extracted with EtOAc (40 mL of χ 2). The organic extracts were dried, filtered, and concentrated to afford 6- (4- (3,5-dichloropyridin-4-ylamino) -7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy) hexanoic acid: 1H NMR (400 MHz, DMSO-d6): δ 10.10 (s, 1H), 8.88 (s, 1H), 8.77 (s, 2H), 7.89 (d, 1H), 7.06 (d, 1H), 4.80 (s 3.95 (t, 2H), 3.90 (s, 3H), 2.22 (t, 2H), 1.76 (m, 2H), 1.55 (m, 2H), 1.39 (m, 2H); MS (ESI): 465. 8

EXAMPLE 12

4- (3,5-Dimethylpyridin-4-ylamino) -8-isobutoxy-7- The title compound was prepared from methyl 3-hydroxy-4-methoxy-2-nitrobenzoate (Example 1, step 1) and 1- bromo-2-methylpropane following the procedures outlined in Examples 1 & 8. 1H NMR (400 MHz, DMS0-d6): δ 9.39 (s, 1H), 8.42 (s, 1H), 8.39 (s, 2H), 7.89 (d, 1H), 7.03 (d, 1H), 4.51 (s , 1H), 3.89 (s, 3H), 3.74 (d, 2H), 2.13 (s, 6H), 2.13 (m, 1H), 0.97 (d, 6H); MS (ESI): 368.2.

EXAMPLE 13 4- (3,5-Dichloropyridin-4-ylamino) -8- (4- (dimethylamino) butoxy) -7-methoxyquinolin-2 (1H) -one .8- (4-Bromobutoxy) -4- (3 , 5-Dichloropyridin-4-ylamino) -7-methoxyquinolin-2 (1H) -one was prepared from 4- (3,5-dichloropyridin-4-ylamino) -8-hydroxy-7-methoxyquinolin-2 (1H) - (example 11, step 1) and 1,4-dibromobutane following the procedure outlined in example 11, step 2. MS (ESI): 485.8.

Step 2

A solution of dimethylamine (1.5 mL, 2M THF, 3 mmol) was added to a solution of 8- (4-bromobutoxy) -4- (3,5-dichloropyridin-4-ylamino) -7-methoxyquinolin-2 ( 1H) -one (146 mg, 0.3 mmol) and DMSO (3 mL). After 2.5h, the reaction was poured into 10% K 2 CO 3 (30 mL) and extracted with dichloromethane (40 mL χ 2). The combined extracts were dried, filtered, concentrated, and purified by silica gel chromatography (1: 0- * 4: 1; dichloromethane: methanol with 1% concentrated NH 4 OH solution) and then reverse phase HPLC (1: 9 -1: 1; acetonitrile: water) to provide 4- (3,5-dichloropyridin-4-ylamino) -8- (4- (dimethylamino) butoxy) -7-methoxyquinolin-2 (1H) -one: 1 H NMR ( 400 MHz, DMS0-d6): δ 10.29 (s, 1H), 8.81 (s, 1H), 8.75 (s, 2H), 7.87 (d, 1H), 7.04 (d, 1H), 4.77 (s, 1H) 3.99 (t, 2H), 3.90 (s, 3H), 2.27 (t, 2H), 2.13 (s, 6H), 1.73 (m, 2H), 1.54 (m, 2H); MS (ESI): 451.0.

EXAMPLE 14.4- (3,5-Dichloropyridin-4-ylamino) -8- (5- (dimethylamino) pentyloxy) -7-methoxyquinolin-2 (1H) -one

The title compound was prepared from 4- (3,5-dichloropyridin-4-ylamino) -8-hydroxy-7-methoxyquinolin-2 (1H) -one (example 11, step 1) and 1,5-dibromopentane following procedures outlined in example 13. 1H NMR (400 MHz, DMSO-d6): δ 9.91 (s, 1H), 8.83 (s, 1H), 8.75 (s, 2H), 7.87 (d, 1H), 7.04 (d, 1H), 4.77 (s, 1H), 3.96 (t, 2H), 3.90 (s, 3H), 2.19 (t, 2H), 2.10 (s, 6H), 1.76 (m, 2H), 1.48-1.32 (m , 4H) MS (ESI): 465.0.

The following compounds may generally be made using the methods described above. It is expected that these compounds when made will have activity similar to those that were made in the above examples.

The following compounds are represented herein using the Simplified Molecular Entry Lineage Entry System, or SMILES. SMILES is a modern chemical notation system, developed by David Weininger and Daylight Chemical Information Systems, Inc., which is built on all major commercial chemical structure design software packages. Software is not required to interpret SMILES text strings, and an explanation of how to translate SMILES into structures that can be found in Weininger, D., J. Chem. Computer Info Know. 1988, 28, 31-36. All SMILES strings used here were generated using Accelry's Pipeline Pilot 6.0. Many IUPAC names used here were generated using CambridgeSoffs ChemDraw 10.0. <formula> formula see original document page 75 </formula> COc 1 ccc2C (= CC (= 0) Nc2c 10CC (-0) N) Nc3c (C) cncc3Cl COc 1 ccc2C (~ CC (~ Ü) Nc2c 1 OCCCCN) Nc3c (F) cncc3F COcJ ccc2C (= CC (~ 0) Nc2c 10CC (-0) N) Nc3c (F) cncc3F NC (= 0) C0c 1 c (0CF) ccc2C (= CC (= 0) Nc 12) N c 3c (F) cncc 3 F COc 1 ccc2 C (= CC (-0) Nc2c 10CC (-0) N) Nc3 c (F) cncc3 Cl COc ccc2C (-CC (-0) Nc2cl OCCCCN) Nc3c (C) cccc3C Cc 1 ccc «(C) and lNC2-CC (-0) Nc3c (0CCCCN) c (0CF) ccc23 CNCCCC0clc (0C) ccc2C (= CC (= 0) Ncl2) Nc3c (C) cccc3C COe 1 ccc2C (= CC (= 0) Nc2c] OCCCCCN) Nc3c (C) cccc3C COe 1 ccc2C (= CC (= 0) Nc2c 10CC (= 0) N) Nc3c (C) cccc3C Cc 1 cccc (C) c 1 NC2 = CC (= 0 ) Nc3c (0CC (= 0) N) c (0CF) ccc23 COc 1 cec2C (= CC (= 0) Nc2c 1 OCCCC (= OM) Nc3c (C) eccc3C COc 1 ccc2C (-CC (-0yNc2c 10CCCC "N) Nc3c (C) cccc3F CNCCCCOe I c (0C) ccc2C (= CC (= 0) Ne 12) Nc3c (C) cccc3F COc 1 ccc2C (= CC (= 0) Nc2cl0CCCCCN) Nc3c (C) cccc3F COe 1 ccc2C (= CC (~ 0> Nc2c 1 OCC (= 0) N) Nc3c (C) cecc3F Ce 1 ACC (F) C 1 NC2 = CC (= 0) Nc3c (0CC (= 0) N) c (0CF) ccc23 COc 1 ccc2C (= CC (= 0) Nc2c 1 OCCCCf = O) N) Nc3c (C) cccc3F COc 1 cc-c2 C (-CC (-0) Nc2c 10CC (= 0) N) N c3 c (C) cc cc3 IC C0c] cc · 2C (-CC (ss0) Nc2cl0CC (-0) N) Nc3c (C) cc (F) c <; 3C COc S ccc2C (= CC (= 0) Nc2d0CC (= 0) N) Nc3c ( C) cc (F) cc3F COc 1 coc2'C (= CC (= 0) Nc2c 10CCCCN) Nc3c (C) cc (O) cc3C C0elccc2C (= CC (= 0) Nc2c 10CC (= 0) N3 Nc3c (C ) cc (0) ce3C COc 1 ccc2C (-CC (-0) Nc2c 10CC (= 0) N) Nc3c (C) cc (0) cc3F COc 1 ccc2C (= CC (= 0) Nc2c 10CC'CCN) Nc3c ( F) cccc3F COcl cec2 C (-CC (t = 0) Nc2 c 10CC (-0) N) Nc3c (F) cccc3F NC (-0) C0c 1 c (0CF) ccc2C (-CC (-0) Nc 12) Nc3c (F) cccc3F COeI ccc2 C (-CC (= 0) Nc2 c 10CC (-0) N) Nc3c (F) ecec 3 Cl COe 1 ccc2C (= CC (= 0) Nc2c 10CC (-0) N) Nc3c (F) cc (F) cc3F COe 1 ccc2C (~ CC (= 0) Nc2c 1 ÜCC (-0) N) Nc3c (F) cc (0) cc3F

CN (C) ACCOc 1 c (0C (F) F) ccc2C (= CC (= 0) * c 12) Nc3c (C) cccc3C <formula> formula see original document page 77 </formula> <formula> formula see original document page 78 </formula> <formula> formula see original document page 79 </formula> CN (CCC [Ni] (C XC) C) C (~ 0) CC CCOc 1 c (0C (F) (F) F ) ccc2C (-CC (-0) Nc i 2) Nc3c (C) and ccc 3 Br

CN (CCC [N +] (C KC) C) C (-D) ACCOCO 1c (0C (F) F) ccc2C (-CC (-0) Nc 12) Ne3c (C) cc cc3Br

COc 1 ccc2 C (= CC (= 0) Nc2c 1 OCCCCCC (s2O) N [C @@ H] (Cc3ccc (0) cc3) C (= 0) 0) Nc4c (C) cccc4Br

CCCN (C) ACC0c c (0C (F) (F) F) ccc2C (CC (= 0) Nc 12) Nc3c (C) cc (F) cc3C COc 1 ccc2 C (= CC (= 0) Nc2 c 1 OCGCCN3CCCCC3 ) Nc4c (C) cc (F) cc4C Cc 1 cc (F) cc (C) c 1 NC2 = CC {= 0) Nc3c (0CCCCN4CCCC4) c (0CF) ccc23 ACCNC (C) ACCOCOcc (0C3) ccc2C (= CC <= 0) Ncl2) Nc3c (C) cc (F) cc3C Cclcc (f) cc (C) € lNC2 ^ C (= 0) Nc3c <0CCCCCn4nccn4) c (0C (F) F) ccc23 Cc 1 cc (f ) cc (C) c 1 NC2 == CC (= 0) Nc3c (0CCCCC0c4ccncc4) c (0CCF) (F) F) ccc23 Cc I cc (F) cc (C) c 1NC2 = CC (= 0) lNc3c (0CCCCCCn4ccnc4 ) c (0C (F) F) ccc23 Cc lcc (F) cc (C) c I NC2 = CC (= 0) Nc3c (0CC (= 0) 0CC [NI = J (C) (C) C) c ( OCF) cce23 CN (C) CCCN (C) C (O) CCCO0c 1 c (0CF) ccc2C (= CC (-0) Nc 12) Nc3c (C) cc (F) cc3C

Cc 1 cc (F) cc (C) c 1NC 2 = CC (= O) Nc3c (0CCCCC (= 0) OCC [N + J (C) (C) C) c (0C (F) (F) F) c cc23

Cc 1 cc (F) cc (C) c lNC2 <; C (= 0) Nc3c (0CCCCC (= 0) N4CCCfC @ B] 4C (= 0) 0) c (0CF) c cc23

C0elccc2C (= CC (= 0) Nc2cl0CCCCCC (= 0) N (C) CCN (C) C) Ne3c (C) c and (F) cc3C

Cc I cc (F) cc (C) c 1 NC2 = CC (= 0) Nc3c (0CCCCCC (= 0) N4CCC [C @ H] 4C (= 0) 0) c (0C (F) (F) F) ccc23

Cc lcc (F) cc (C) and 1 KC2h: C (= 0) Nc3c (0CCCCCCX4) N [C @@ H] (Cc4ccccc4) C (= 0) 0) c (OCF) ccc23

Cccc (F) cc (F) c NC2 = CC (= 0) Nc3c (OCCCCn4cnnn4) c (0C (F) F) ccc23

Cc 1 cc (F) cc (F) c I NC2 = CC (-0) Nc3c (OCCCCOc4ccncc4) c (OC (F) (F) F) ccc23

COc 1 ccc2 C (-CC (-0) Nc2c 10CCCCO [C @@ H] 3 O [C @ H] (C0) EC @@ H] (O) EC @ H] (0) [C @ H] 30) Nc4c (C) cc (F) cc4F

ACCNC (C) ACCOCOc 1 c (0C (F) F) ccc2C (-CC (= 0) Nc 12) Nc3c (C) cc (F) cc3F Cc 1 CC (F) CC (F) Cl NC2-CC (= 0) Nc3c (0CCCCC0c4ccncc4) c (0CF) ccc23 COc 1 ccc2C (= CC (= 0) Nc2cl OCCCCCCN) Nc3c (C) cc (F) cc3F <formula> formula see original document page 81 </formula> <formula> formula see original document page 82 </formula> <formula> formula see original document page 83 </formula> C0clccc2C (-CC (~ 0) Nc2cl 0CCCCCC (~ 0) N [Cr «}! Il; (Cc3ccccc3) C (~ 0) 0) Nc4c (C) cc (0) cc4C

Cc 1 cc (0) cc (C) and I NC2 = CC (= 0) Nc3c (OCCCCCC (-0) N (C (R (H) (C) C (= 0) 0) c (0C (F) (F) F) ccc23

Cc 1 CC (O) CC (F) C lKC2-CC (-0) Kc3c (0CCCCn4cccn4) c (0CF) ccc23

COCCOCCCCOc I c (0C (F) (F) F) ccc2C (-CC (-0) Nc 12) Nc3c (C) cc (0) cc3F CCCN (C) ACCOCOc 1 c (0CF) ccc2C (= CC (= 0 ) Nc 12) Nc3c (C) cc (0> cc3F Cc 1 CC (O) CC (F) C 1 NC2 = CC (= 0) Nc3c (0CCCCCn4cccn4) c (0C (F) F) ccc23 Cc I cc (0 ) cc (F) c 1 NC2-CC (= 0) Nc3c (0CCCCCn4ncnn4) c (0C (FXF) F) ccc23 CNCCCCCCOc 1 c (0CF) ccc2C (= CC (= 0) Nc 12) lSlc3c (C) cc ( 0) ce3F C0CC0CCCCCC0clc (0C ') ccc-2C (= CC (= 0) Ncl'2) Nc3c (C) c5c (0) cc3F Cc I cc (0) cc (F) and 1 NC2 = CC (= 0) Mc3c (0CC (= 0> N) c (0C (F) (F) F) ccc23 COc 1 ccc2C (= CC (= 0) Nc2c 10CC (= 0) N [C @@ H] (CC (C) C ) C (-0) 0) Nc3c (C) cc (0) cc3 F

Cc 1 cc (0) cc (F) clNC2 ~ CC (= 0) Nc3c (0CC (~ 0

Cc 1 cc (0) cc (F) c 1NC2 = CC (= 0) Nc3c (0CCCC (= 0) N4CCNCC4) c (0C (F> F) ccc23 CKlCCN (CCl) C (HD) CCC0c2c (0CF) ccc3C ( = CC (== 0) Nc23) 'Nc4c <C) cc (0) cc4F Cc 1 cc (0) cc (F) c 1 NC2 = CC (= O) Nc3c (0CCCC (= 0) N [C @@ H] (CCCNC (= N) N) C (= 0) 0) c (0C (F) (F) F) ccc23 COc 1 ccc2C (-CC (= 0). Nc2c 10CCCCC (-0) N3CCNCC3) Nc4c ( C) cc (0) cc4F

CC (C) [C # H] (NC (= 0) ACC0c Ic (0CF) ccc2C (= CC (= 0) Nc 12) Nc3c (C) cc <0) cc3F) C (= 0) 0

COc 1ccc2C (= CC '(= 0) Mc2c 10CCCCCCX = 0) NCC [N + J (C) (C) CyN c3 c (C) cc (0) cc3 F Ccl cc (0) cc (F) cl NC2 = CC (-0) Nc3c (OCCCCCC (-0) NIC @@ H] (Cc4, gc <0) cc4) C (= 0

} 0) C (0C (F) P) GCC23

CCN (CC) CCOc1C (0C} ccc2C (-CC (-0) NC12) Nc3C (C) Cc 1 cc (0) cc (C1) c INC2 — CC (-0) Nc3c (0CCCCN4CCCCC4) c (0C (FXF) F) ccc23 Cc 1 cc (0) cc (Cl) cl NC2 = CC (-0) Nc3c (0CCCCN4CCC (F) C4) c (0C (F) F) ccc2 3 CCNCCCCCOcI c (0CF) ccc2C (~ CC (- 0) Nc 1 2) Nc3c (C) cc (0) cc3CI CCCN (CT) ACCOCOc1c (0C (F) F) ccc2C (~ CC (~ 0) NC 12) NC3c (C) CC (0) CC3CI COc 1ccc2C ( = CC (= 0) Nc2c 10CCCCCn3cnnc3) Nc4c (C) cc (0) cc4Cl <formula> formula see original document page 85 </formula> <formula> formula see original document page 86 </formula> <formula> formula see original document page 87 </formula> CCNCOCCCCCCOc I c (0C (F) (F) F) ccc2C (CC {= 0) Nc 12) Nc3c (C) cc (cc3Cl) C (0) 0 COCCOCCCCCCOc I c (0C) ccc2C (-CC (-0) Ncl 2) Nc3c (C) cc (cc3Cl) C (= 0) 0 Cc 1 cc (cc (Ct) c 1 JvC2 ~ CC (~ 0) Nc3c (0CCCCCCCCCCCC0CC0) c (0C (F ) F) ccc23) C (= 0) 0

CN (CCP 3 + 3 (CKC) C) C (-0) C0Clc (0C (F) (^ F) ccc2C (-CC (HD) NcJ2)! Nc3c (C) cc (cc3C1) C (= 0) 0

Cclcc (cc (CI) clNC2 = CC (= 0) Nc3c (OCCCC (-O) N4CCNCC4) and {0C (F) F) ccc23) C (= O) O

Cc 1 cc (cc (C!) And 1 NC2 = CC (-Ü) Nc3c (0CCCCC (= 0) NCC (= 0) 0) c (0C (F) F) ccc23) C (-0) O

Cc 1 cc (cc (Cl) cl 1 C 2 H 2 C (= 0Wc 3c (OCCCCO (= O) N (C @@ H 3 Cl 4 ccccc 4) C (HD) O 4 (0CF) ccc 23) C (= 0) 0

CSCC [H-crã (NC (= 0) ACC0c1 c (0C (F) (F) F) ccc2C (= CC (= 0) Nc2) Nc3c (C) cc (cc3C1) C (= 0) 0 ) C (= 0) 0

CN1 CCN (CC I) C (~ 0) ACCOc 2c (0CF) ccc 3 C (-CC (~ 0) Nc 23) Nc 4c (C) cyclic C 4 (C) -0

COc 1 cce2C (= CC (= 0) Nc2 and 10CCCCCC (= 0) N [C @@ H] (C0) C (= 0) 0) Nc3c (C) cc (cc3 CI) C (= 0) 0

CN (C) ACCOc 1c (0CF) ccc2C (= CC (= 0) Nc 12) Nc3c (C) ce (cc3Br) C (= 0) 0 COe 1 ccc2C (= CC (= 0) Nc2c 10CCCCCN3 CCOCO) Nc4c (C> ce4Br) C (-0) 0 Ce I cc (cc (Br) and I NC2 = CC (= 0) Nc3c (OCCCCCOCCOCCO) c (OCF) ccc23) C (= 0) 0 Ce I cc (cc ( Br) c lNC2 = CC (= 0) Nc3c (0CCCCCCN) c (0C (F) F> ccc23) C {= 0) 0 C0clccc2C (= C'C (== 0 ')' Nc2cl0CCCCCCM3CCCC3) Nc4c (C) cc (cc4Br) C (= 0) 0 Cclcc (cc (Br) clNC2 = CC (= 0) Nc3c (OC'CCCCCn4cnnn4) c (OC (F) (F) ccc23) C (= O) O COc 1 ccc2C (= CC (= 0) Nc2cl OCC (= 0) N [C @@ H] (Cc3c [iiH] c4cc € cc34> C (= 0) 0) Nc5e (C) cc (cc5 Br) C (-0) 0

Cc 1 cc (cc (Br) c INC2 = CC (-0) Nc3e (0CC (-0) N [C (aif.H] (Cc4c [nH] c5ccccc45) C (= 0) 0) c (OCF) ccc23 ) C (-0) 0

(- CC (-0) Nc2c 10CCCCC (-0) N3CCN (C) CC3) Nc4c (C) cc (cc4Br) C (-0) O

Cclcc (cc (Br) clNC2 = CC (= 0) Nc3c (0CCCCCC (= 0) N) c (0C (F) F) ccc23) C (= 0) 0 <formula> formula see original document page 89 </ formula > Fc I ACC (CI) C 1 NC2OC (O) Nc3c (0CCCCn4nccn4) c (0C (F) (F) Fc) ccc23 COCCOCCOCCOCCCCOc 1 c {0C (F) F) ccc2C (CC (O) Nc12) Nc3c (F ) cccc3CI COc 1 cec2C (™ CC (0) Nc2 c .1 OCCCCCN (C) C) Nc3c (F) cccc3Cf Fc 1 cccc (CI) c 1 NC2 = CC (= 0) Nc 3 c (OCCCCCN4CCCC (F) ( F) C4) c (OC (F) (F) F) ccc23 FCOc 1 ccc2C (™ CC (-0) Nc2c I OCCCCCOc3ccccn3) Nc4c (F) cccc4CI

OCCOCCOCCCCCCOc 1 c (0C (F) (F) F) ccc2C (-CC (= 0) Ncl 2) Nc3c (F) occc3Cl C: N (CCC [N + J (CXC) C) C (-0) COc tc (0CF) ccc2C '; C (O) Nc t2) Nc3c (F) cccc3CI CN1 CCN (CC I) C (= 0) C0c2c (0C (F) F) ccc3C (= CC (-0) Nc23) Nc4c (Fc ccc4CI COc 1 ccc2C (~ CC (~ 0) Nc2 c 10CC (= 0) N [C @@ H] (ACPC) C (== 0) 0) Nc3c (F) cccc3Ci COc 1 ccc2C (= CC (= 0) Nc2c 1OCC CC (= 0) N [C @@ H] (C) C (= 0) 0) Nc 3c (F) c ccc3 C t

0C (K>) [C @ H] (Cclccc (0) ccl) Na ^) ACCk2 ^ 0CF) ccc3C (<: C <-0) Nc23) Nc4c (F) eccc4CI

C [C (S) @ H] (0) f C @ H] (NC (^) CCCO0c (0C (F) F) ccccC (-3Cl) C (= 0) 0

CN (CC |> 1 +] (C) (C) C) C <= 0) ACCdclc (0CF) ccc2C (-CC (= 0) Nc 12) Nc3c (F) cccc3Ct 0C (O) CNC (O) CCCLOc 1 c (0C (F) F) ccc2C (= CC (-0) Nc 12) Nc3c (F) cccc3CI C [C @@ H] (0) [C @ B] (NC (= 0) ACC0c c (0C ( F) (F) F) ccc2C (= CC (= 0) Nc 12) Ne3c (F) cccc3CI) C (= 0) 0

OC (O) [C @ H] (Cc 1 cnc [nH] I) NC (O) COUNC0c2 c (OC (F) (F) F) ccc 3 C (= CC (0) Nc2 3) Mc4c (F) cccc4CI

NC (= 0) C [C @ H] (NC (= 0) COUNC0cIc (0C (F) F) ccc2C (= CC (-0) Ncl2) Nc3c (F) cccc3 Ci} C (O) O

C0clccc2C (= CC (= 0) Mc2cl0CCCC0c3cccnc3) Nc4c (F) cccc4Br FC (F) Oc1 ccc2C (-CC (= 0) Nc2c 1 OCCCCCN3CCC (F) CCc4C (F) cccc4Br FCOc 1 ccc2C ) Nc2c 10CCCCC0c3 ccccm3) Nc4c (F) cccc4Br CNCCCCCCOc 1 c (0C (F) F) ccc2C (-CC (O) Nc 12) Nc3 c (F) cccc3 Br COCCN (C) CCCCCCOc I c (0C (F) ( F) F) ccc2C (= CC (O) Nc 12) Nc3c (F) cccc3Br FCOc I ccc2C (= CC (O) Nc 2c I OCCCCCCN3CCC (FXF) C3) Nc4c (F) cccc4Br NC (O) COc 1 and (0C (F) F) ccc2C (OC (O) Nc 12) Nc3c (F) cccc3Br CC [C (a H H) (C) [C @ H] (NC (O) COc 1 c (OC F) ccc 2C (~ CC (0) .Nc 12) N c3 c (F) eccc 3 Br) C (= 0) 0 <formula> formula see original document page 91 </formula> <formula> formula see original document page 92 </ formula> <formula> formula see original document page 93 </formula> <formula> formula see original document page 94 </formula> <formula> formula see original document page 95 </formula> (F) (F) F) ccc2C (-CC (= 0) Nc 12) Nc3c (F) cc (.cc3F) C (= 0) 0 CÕclccc2C (-CC (-Ü) Nc2cl0CCCC0CC0CCO) Nc3c (F) cc ( cc3F) C (= 0) 0 COCCOCCOCCOCCCCOc lc (OC F) eoc2C (= CC <= 0) Ne 12) Nc3c (F) cc (c c3F) C (-0) 0 0C (= 0) clcc (F) c (NC2 = CC (= 0) Nc3c (0CCCCCn4ccnc4) c (OC (F) F) ccc23) c (F) cl 0C (-0) cl cc (F) c (NC2-CC (= 0) Nc3c (0CCCCCrv4cnnc4) c (0CF) ccc23) c (F) cl

COCCOCCOCCOCCCCCOc 1 c (0C) ccc2C (CC (-0) Nc 12) Nc3c (F) cc (cc3F) C (0) 0 COc 1 ccc2C (-CC (-0) Nc2c 10CCCCCCN3CC0CC3) Nc4c (F) cc (cc4F) C (-0) 0 0C (= 0) c 1 cc (F) c (NC2 = CC (= 0) Nc3c (OCCC € CCN4CCOCC4) c (OC (F) F) ccc23) c (F) c 1 COc 3 ccc2C (= CC (= 0) Nc2c 10CC (~ 0) NCC pN +] (C) (C) QNc 3 c (F) ee (c and 3 F) C (~ 0) 0 CN (C) CCN (C) C (= 0) COc 1 c (OCF) ccc2C (= CC (= 0) Nc 12) Nc3e (F) c '(cc3 f) C (= 0) 0 CN (CCC [N +] (CXC) C) C < K>) CCC (kJc (OC (FXF) F) ccc2C (^ C (H3) Hcl2) Nc3c (F) cc (cc3F) C (= 0) 0

0C (-0) clcc (F) c ("NC2-CC (-0) Nc3c (0CCCC (-0) N4CCNCC4) c (OC (F) F) ccc23 ') c (F) cl

COc 1 ccc2C (= CC (~ 0) Nc2 c 1 CCCCCC (^ Ü) N [«§Ã ^ (= 0) 0

0C (= 0) [C @@ H] ICCCNI C (= 0) ACC0c2c (0C (F) F) ccc3C (= CC (= 0) Nc23) Hc4c (F) cc (cc4F) C (= 0) 0

C [C @@ HJ (0) [C @ e] (NC (= 0) ACCOUNT (0C (F) (F) F) cec2C (= CC (= 0) Nc 12) Nc3c (F) cc (cc 3 F) C (-0) 0) C (-0) 0

C0cJccc2C (= CC (= 0) Nc2c! 0CCCCCC (= 0) N [C @ # H] (CC (C) OC (= 0) 0) Nc3c (F) cc (cc3F) C (~ 0) 0

CS (X (C @ B) (NC (= 0) COCC.CX) c 1 c (OC (F) F) ccc2C (KrC (H3) Ncl2) Nc3c (F) cc (cc3F) C (= 0) 0 ) C (-0) 0

CSCC [C @ H] (NC (= O) ACCOc 1c (0C (F) (F) F) cce2C (= CC (= 0) Nc 12) Nc3c (F) cc (cc3 F) C (-0) 0) C (-0) 0

COc 1 ccc2C (-CC (-0) Kc2c 10CCCCn3nccn3) Nc4c (F) cc (cc4CI) C (= 0) 0 OCCOCCCCOc I c (OC (F) F) ccc2C (-CC (-0) Nc 12 ) Nc3c (F) cc (cc3CI) C (K)) 0 0C (-0) clcc (F) c (NC2-CC (= 0) Nc3c (0CCCCCN4CCC (F) (F) CC4) c (0C (F) (F) F) ccc23) c (CI) cl

COc 1 ccc2C (= CC (= 0) Nc2c 10CCCCCn3cccn3) Nc4c (F) ce (cc4CI) C (= 0) 0 <formula> formula see original document page 97 </formula> NC (-0) C [C @ H ] (NCC-0) COc I c (0C (F) F) ccc2C (-CC (= 0) Nc 12) Nc3c (F) cc (cc3Br) C (-0) 0) C (-0) 0

CC (C) [C @ HJ (NC (= 0) CCC0c1 c (ÜC (F) (F) F) ccc2C (-CC (-0) Nc I 2) Nc3c (F) cc (cc3 Br) C (= 0) 0) C (= 0) 0

NCCCC [C (1 H] (NC (-0) CCCOc! C (0CtF) F) ccc2C <-CC (-0) Ncl 2) Nc3c (F) cc (cc3Br) C (= 0) 0) C ( = 0) 0

COc 1 ccc2C (-CC (-0) Nc2c 10 € CCC (-0) N [Cfe @ H] (CC (-0) N) C (K)) 0) Nc3c (F) cc (c c3Br) C ( = 0) 0

COc 1 ccc2C (-CC (-0) Nc2c 1 OCCCCC (-0) N3CCNCC3) Nc4c (F) cc (cc4Br) C (-0) 0 CC (C) C [C @ H) (NC (= 0) 1 c (0C (F) F) ccc2C (= CC (= 0) Nc 12) Nc3 c (F) and c (ec 3 Br) C (= 0) 0) C {= 0) 0

CC [C @ H] (C) IC (®H) (NC (= 0) ACC0cc (0C (F) (F) F) ccc2C (= CC (= 0) Nc) 2) Nc3c (F) cc (cc3Br ) C (-0) 0) C (= 0) 0

CN (C) CC0C (= 0) ACCOCOc t c (OCIF) (F) F) ccc2C (= CC (= 0) N c 12) Nc3c (F) cc (cc3Br) C (^ 0) 0

C [C # @ H] (0) [C @ H] (NC (= 0) ACCCOccl (0CF) ccc2C (= CC (= 0) Nc] 2) Nc3c (F) cc (c c3Br) C (= 0) 0X: (= 0) 0

C0clccc2C (= CC (^) Nc2cl (K: ACPCC (= 0) N [C (^ / # HKCCX <)) iN) C (<>) 0) Nc3c (Fc (cc3Br) C (-0) 0

CCCNCCCCOc I c (0C) ccc2C (-CC (= 0) Nc 12) Nc3c (Cl) cccc3CI

CCCKCCCCOclc (OC (F) F) ccc2C (= CC (= C>) Ncl2) Nc3c (CI) cccc3CI CCCNCCCCOc 1 c (0C (F) F) ccc2C (-CC (= 0) Nc12) Nc3c ( Cl) cccc3CI OCCOCCOCCOCCCCO c (OCF) ccc 2C (= CC (= 0) Mc 12) Ne3c (Cl) eccc3Cl COc 1 ccc2C (-CC (-0) Nc2c .1 OCCCCCNC (-N) N) Nc3c (Cl) cccc3CI FC (F) (F) Oc lccc2C (= CC (= 0) Hc2cl0CCCCCM3CC0CC3) Nc4c (C) cccc4Cl FCOclccc2C (-CC (-O) Nc2clOCCCCCo3cccc3) Nc4o (Cl) cccc4Cl ACN (C) ) F) cce2C (-CC (-0) Nc 12) Nc3c (C!) Cccc3CI FCOcl ccc2C (-CC (-0) Nc2cl0CCCCCCOc3cccnc3) Nc4c (CI) cccc4C [CN (C) CCOC (~ 0) CQc 1 c ( OCF) ccc2C (= CC (™ 0) Nc 12JNc3 c (C1) cccc3Cl COc 1 ccc2C (-CC (^ 0) Nc2c 10CC <®0) N (C) CCCN (C) C) Nc3c (Cf) cccc3CI < formula> formula see original document page 99 </formula> <formula> formula see original document page 100 </formula> <formula> formula see original document page 101 </formula> CCCNCCCCCCOc 1 c (0C (F) F) ccc2C ( = CC (-0) Kc 12) Nc3c (Cl) cc (0) cc3Cl COc 1 ccc2C <~ CC ('0) Nc2c 1OCCCCCCN 3CCC (F) CC3) Nc4c (CI) cc (0) cc4CI Oc 1 cc (CI ) c (NC2-CC (-0) Nc3c (0CCCCCC0c4cccnc4) c (0C (F) (F) F) ccc23) c <CI) c 1 COc 1 ccc2 C (= CC (= 0) Nc2c 10CC (= 0) 0CCN (C) C) Nc3c (Cl) cc (0) cc3C [0C (-0) CNC (-0) C0c 1 c (0C (F) (F ) F) ccc2C (£ 2CC (-0) Nc 12) Nc3c (C]) cc (0) cc3C I COc 1 ccc2C (-CC (-0) Nc2c 10CCCC (-0) NCC (= 0) 0) lSc3c ( CI) cc (0) cc3Cl CSCC [C @ B] (NC (= 30) CCCO 1 c (OC (F) F) CO 2 C (-CC (-O) Nc 12) Nc 3 c (Cl) cc (0) cc 3 Cl) C (= 0) 0

NCCCC (C @ H] (NC (-0) CCCOc] c (0C (FXF) F) ccc2C (-CC (= O> Nc i2) Nc3c <Cf) cc <0) c c3CI) C (= 0) 0

0C (<^) [C @ H) (Cclcnc [nH] 1) NCe0) CCC0c2c (0CF) ecc3C (= CC (= 0) Hc23) Nc4c (Cl) cc (0) cc4CI

NC (= 0) ACC0cc (0CF) ccc2C (= CC (-0) Nc! 2) Nc3c (Cl) cc (0) cc3CI 0C (= 0) CNC (= 0) ACC0c 1 and (0C (F) F) ccc2C (= CC (= 0) Nc 12) Nc3c (Cl) cc (0) cc3CI C [M ^ 3 (CXC) CCNC4 = 0) ACCOC1C (0CF) CCC2C (= CI

COc 1 cec2C (= CC (= 0) Nc2c 10CCCCCC (= 0) NCC (= 0) 0) Nc3 c (CI) cc (0) cc3 Cl 0C (= 0) [C @ H] (Cc I cccce 1) NC (= 0) ACCO0c2c (0C (F) F) ccc3C (= CC (= 0) Ne23> Nc4 c (CI) cc (0) cc4Cl

CCN (CC) ACCOClc (OCF) ccc2C (-CC (= sO) Ncl2) Nc3c (CI) ccCO) cc3B: r

COe 1 ccc2C (-CC (-0yNc2c 10CCCCN3CCCCF) (F) C3) Nc4c (CI) cc (0) cc4Br Oc (cc) c (NC2 = CC (= 0) Nc3c (0CCCC0c4cccnc4) c (0C (F) F) ccc23 ') c (Br) c 1 C0c.lccc2C (= CC (= 0) Nc2cl0CCCCClSf) Nc3c (Cl) cc (0) cc3Br Oc 1 and c (NC2s; CC (= 0) Nc3c (0CCCCCN4CCC .C (F) C4) c (0C (F) F) ccc23) c (Br) cl COCCOCCCCCOc 1 c (0CF) cec2C (= CC (= 0) Mc 12) Me3c (Ci) ce (0; cc3Br

ACCN (C) CCCCCCOc c (0C (F) F) ccc2C (= CC (-0) Nc 12) Nc3e (Cl) cc (0) cc3Br Oc (cc) c (NC2-CC (-0) Nc3c ( 0CCCCCC0c4ccccn4) c (OCF) ccc23) c (Br) c I Oc 1 cc (C]) c (NC2-CC (-0) Nc3c (OCC (0) N4CCNCC4) c (OC (F) (F) ccc23 ) c (Br) c I COe 1 ccc2C (= CC (= 0) 1S'c2c 1 OCC (-0) N [C # @ H} (CCSC) C (-0) 0) Nc3c (Cl) cc (0) cc3 Br <formula> formula see original document page 103 </formula> <formula> formula see original document page 104 </formula> CCN (CC) CCCCCCOc I c (0C (F) F) ccc2C (= CC (= 0) Nc 12) Nc3c (Br} cccc3Br FC (F) (F) Oc I ccc2C (~ CC (~ 0) Nc2 c 1OCCCC CCN3 CCOCC3) Nc4c (Br) cccc4Br FCOc 1 ccc2C (-CC (= 0) Ne2c 1 OCCCCCCn3cccn3) Nc4e (Br) cccc4Br CN1 CCN (CC 1) C (= 0) C0c2c (0C (F) F) ccc3C (== CC (= 0) Nc23) Nc4c (Br) cccc4Br C [C @ H] (NC (- 0) C0cl and (0CF) ccc2C (= CC (= O) Ne 12) Nc3c (Br) cccc3Br) C (0) 0 C [N +] (CXC) CCNC '(= 0) CCC0c I c (0CF) ccc2C ( = CC (= 0) 1s5c 12) Nc3c (Br) cccc3Br C [C @ H] (NC (-0) CCC0c I c (OC (F) F) cc c 2 C (^ CC (= 0) Nc 12) Nc3c (B r) cc c c3 B r) C (-O) O

0C (= 0) [C @ H1 (Cclc [nH] c2c0cccl2) NC (= 0) CCC0c3c (0C (FXF) F) ccc4C (= CC (= 0) N c34) Nc5c (Br) cccc5Br

C [N +] (CXC) CCNC (= 0) ACC0cIc ^ 0CP) ccc2C (= <^ C (= 0) Nc.l.2) Nc3c (Br) cccc3Br C0clccc2C (= CC (= 0) Nc2cI. 0CCCCC (= 0) N [C @@ H] (CC (C) C) C (== 0) 0) Nc3 c (Br) ccc c3Br

CN (C) CCN (C) C (= 0) ACCOcIc (OC (F) (F) F) ccc2C (= CC (= O) Nci2) Nc3c (Br) cccc3 Br

CN (CC [N +] (C) (C) C:) C (-0) CCC: CC0cc 1 (0C (F) F) ccc2C (<; C (-0) Nc 12) Nc3c (Br) ccc c3Br

FCOc 1 ccc2C (= CC (= 0) Nc2c 10CCCCCC (= 0) N3CCNCC3) Nc4c (Br) ccec4Br

C0c1ccc2C (<: C (= 0) Nc2cl0CCCCCC (-0) N [C @@ H] (CC (K)) N) C (<)) 0) Nc3c (Br)

cccc3Br

FCOc I ecc2C (-CC (-0) Nc2c I OCCCCCN3CCCC (FXF) C3) No4c (Br) cc (F) cc4Br FC (F) Oc 1ccc2C (= CC (= 0) Nc2cl0CCCCN3CCC (.F) (F) CC3) Nc4c (Br) cc (F) cc4Br C0CCN (C) ACCOC0c] c (OC (F) F) ccc2C (= CC (= 0) Ncl2) Nc3c (Br) cc (F) cc3Br C0clccc2C (= CC (= 0) Nc2cJ0CCCCCN3CC0CC3) Nc4c (Br) cc (F) and c4Br Fc I cc (Br) c (N'C 2 = CC (= 0) N c3 c (0CCCCCn4cc cc4) c (OC (F) (f) c cc2 3 ) c (Br) c 1 FCOc lccc2C (ssCC (-0) Nc2c 10CCCCCn3 cmn3) Nc4c (Br) cc (F) cc4Br CNCCCCCCOc I c (0CF) ccc2C (= CC (-0) Nc 12) Ne3c (Br) cc (F) cc3Br FC (F) Oc I ccc2C (-CC (= 0) Nc2c 1 OCCCCCCo 3ccim3) Nc4c (Br) and c (F) cc4Br NCCCC [C @ H] (NC (= 0) C0c 1 c (OCF) ccc2C (= CC (= 0) Nc 12) Nc3c (Br) cc (F) cc3 Br) C (- 0) 0 <formula> formula see original document page 106 </formula> <formula> formula see original document page 107 </formula> COc1ccc2C (= CC (= O) Nc2c1OCCCC (-O) N [C @@ H] (CO) C (-O) O) Nc3c (Br) cc (cc3Br) C (-O) O

CN (C) CCNC (= O) ACCOc1c (OCF) ccc2C (= CC (-O) Nc12) Nc3c (Br) cc (cc3Br) C (= O) O

CN (CC [N +] (C) (C) C) C (= O) ACCOCO1c (OC (F) (F) F) ccc2C (= CC (= O) Nc12) Nc3c (Br) cc (cc3Br) C ( -O) O

C [C @ H] (NC (-O) ACCOc 1c (OCF) cec 2 C (-CC (-O) Nc 12) Nc 3c (Br) cc (cc 3 Br) C (-O) O) C (= O) O

COc1ccc2C (= CC (= O) Nc2c1OCCCC'CC (= O) N [C @@ H] (ACPC) C (= O) O) Nc3c (Br) c c (cc3Br) C (= O ') O

CCN (CC) ACCOc1c (OC (F) F) ccc2C (= CC (= O) Nc12) Nc3c (C) cncc3C

ACCN (C) ACCc1c (OCF) ccc2C (= CC (= O) Nc12) Nc3c (C) cncc3C

COc1ccc2C (= CC (= O) Nc2c1OCCCCN3CCCC (F) (F) C3) Nc4c (C) crt cc4C

Cc1cncc (C) c1NC2s = CC (= 0) Nc3c (0CCCCn4nccn4) c (0C (F) F) ccc23

Cclcncc (C) c1NC2 = CC (= 0) Nc3c (OCCCCn4cncn4) c (OC (F) (F) F) ccc23

CNCCCCC0c1c (OC (F) F) ccc2C (= CC (-O) Nc12) Nc3c (C) cncc3C

COCCN (C) ACCOc1c (OCF) ccc2C (-CC (-O) Nc12) Nc3c (C) cncc3C

COc1ccc2C (= CC (= O) Nc2c1GCCCCCN3CCC (F) CC3) Nc4c (C) cncc4C

Cc1cncc (C) c1NC2 = CC (= O) Ne3c (OCCCCCn4nccn4) c (OC (F) (F) F) ccc23

Cc1cncc (C) c1NC2 = CC (= O) Nc3c (OCCCCCOc4cccoc4) c (OC (F) F) ccc23

COc1ccc2C {-CC (-O) Nc2c1OCCCCCCN (C) C) Nc3c (C) cncc3C

CCNCCCCCCOc1c (OCF) ccc2C (= CC (-O) Nc12) Nc3c (C) cncc3C

CCN (C) CCCCCCOc1c (OC (F) F) ccc2C (= CC (= O) Nc12) Nc3c (C) cncc3C

ACNN (C) CCCCCCOc1c (OC (F) (F) F) ccc2C (= CC (= O) Nc12) Nc3c (C) cncc3C

C [C @ H] (NC (= O) COc1c (OC (F) F) ccc2a = CC (= O) Nc12) Nc3c (C) cncc3C) C (= O) O

Cc1cncc (C) c1NC2 = CC (= O) Nc3c (OC-C (= O) K4CCC [C @ H] 4C (= O) O) c (OC (FXF) F) cc c23

COc1cc e2C (= CC (= O) Nc2c1OCC (= O) N [C @@ H] (Cc3cceec3) C (= O) O) Nc4c (C) cncc4 C

C [C @@ H] (O) [C @ H] (NC (O) COc1c (OCF) ccc2C (= CC (= O) Nc12) Nc3c (C) cncc3C) C (O) O

Cc1cncc (C) c1NC2 = CC (K)) Nc3c {OCCCC (= O) OCC [N +] (C) (C) C) c (OCCF) F) ccc23 <formula> formula see original document page 109 </formula> <formula> formula see original document page 110 </formula> <formula> formula see original document page 111 </formula> <formula> formula see original document page 112 </formula> C [C @@ I]] (0) [C (1)] IJ (NC (-0) ACCOc 1c (OC (F) (F) F) ccc2C (-CC (= O) Nc 12) Nc3c (C) cncc3Br) C (0) 0

COc 1 ccc2C (-CC (-0) Nc2c 1OCCCC C (= O) N [C (@i @: H] (Cc3cnc [nHJ3) C (= O) O) Nc4c (C) cncc4Br

CN (C) CCNC (K)) ACC0c 1 c (OC (F) (F) F) ccc2C (-CC (-O) Nc 12) Nc3c (C) cncc3 Br CN (CCC [N + 3 (CXC)) € ) C (= 0) ACCOCOc I c (0C (F) F) ccc2C (= CC (= 0) Nc'2) Nc3c (C) cn cc3Br

Cc 1 CtiCC (Br) CI NC2-CC (= O) Nc3c (0CCCCCC (= 0) N4CCNCC4) c (0CF) ccc23 COc 1 ecc2C (~ CC (~ 0) Nc2c 10CCCX: CC (-0) N3CCC [C4] H] 3C (-0) 0) Nc4c (C) cncc4 Br

FCOcl ccc2C (= CC (= 0) N c2c 1OCCCCN 3CCCCC3) Nc4c (F) cncc4 F FC (F) 0cIccc2C (= CC (-0) Nc2cJ0CCCCN3CCCC (F) C'3) Nc4c (F) ciicc4F FCcCC2 (F) (F) F) ccc3C (= CC (= O) Nc23) Nc4c (F) cncc4F) Cl COc 1 cec2C (= CC (= ü) Nc2c 1 OCCCCn3nccn3) Nc4c (F) cncc4F ççc ^ COUNC0c4c ^ 0C ( F) (FW) ccC (C (s = O-) Nc42) Nc3c (F ') cncc3F CCN (C) ACCOCOcc (0C (F) F) ccc2C (= CC (= O) Nc 12) Nc3c ( F) cncc3F COCCN (C) ACCOCOe lc (0C) ccc2C (= CC (= O) Nc 12) Nc3c (F) cncc3F FCOcl ecc2C (= CC {= O) Ne2e 10CCCX-Cn3 cry nc3) Nc4c (F) and nee4F COCCN (C) CCCCCCOc I c (0C) ccc2C (= CC (= O) Nc 12) Nc3c (F) cncc3F FCOclcc02C (-CC (-O) Nc2clOCCCC: CCN3CCC (F) CC3) Nc4e (F) cnec4F FclciKc (F ) c1 NC2-CC (-O) Nc3c (0CCCCCCn4ncnn4) c (0C (F) (F) F) ccc23 FC (F) Oc1 ccc2C (= @ C (-O) Nc2cl 0C) ccc2C (= CC (= O) Ncl2) Nc3c (F) cncc3F C [N +] (C) (C) CCNC (-O) CQe 1 c (0CF) ccc2C (= CC (= O) Nc 12) Nc3c (F) cncc3F COclccc2C (= CC (K)) Nc2cl0CC (-O) N (C) CCC {N +] (CXCK) Nc3c (F) cncc3F

CC (C) C [C @ H] (NC (-O) COc I c (OC (F) (F) F) ccc2C (-CC (= O) Ncl 2) Nc 3e (F) cncc 3 F) C {= O )THE

0C (K)> [C @ H] (Ce I c [nH] c2cccccl 2) NC (- = O) COc3c (OCF) ccc4C (= CC (-O) Nc34) Nc5 c (F) cncc5F

OC (sO) [C @ H] (Cc I cnc [nH] I) NC (-O) COc2c (OC (F) (F) F) ccc3C (= CC (= O) Nc23) Nc4c (F) cnec4F < formula> formula see original document page 114 </formula> <formula> formula see original document page 115 </formula> <formula> formula see original document page 116 </formula> <formula> formula see original document page 117 </ formula > OC (= O) [C @ H] (Cclc [nH] c2ccccc12) NC (= O) CCCOc3c (OCF) ccc4C (= CC (= O) Nc34) N c5c (Cl) cncc5Cl

OC [C @ H] (NC (= O) CCCOc1c (OC (F) (F) F) ccc2C (= CC (= O) Nc12) Nc3c (Cl) cncc3Cl) C (= O) O

COc1ccc2C (-CC = O) Nc2c1OCCCC (= O) N [C @@ H] ([C @@ H] (C) O) C (= O) O) Nc3c (C1) cncc3Cl

OC (= O) C [C @ H] (NC (= O) CCCOclc (OC (F) F) ccc2C (= CC (= O) Nc12) Nc3c (C1) cncc3Cl) C (= O) O

OC (= O) CNC (= O) ACCOc1c (OC (F) (F) F) ccc2C (= CC (= O) Nc12) Nc3c (Cl) cncc3C1

NCCCC [C # H1 (NC (= O) ACCOccl (OCF) ccc2C (CC (= O) Nc12) Nc3c (Cl) cncc3Cl) C (= O) O

OC (= O) CC [C @ H] (NC (= O) ACCOc1c (OC (F) F) ccc2C (= CC (= O) Nc12) Nc3c (Cl) cncc 3Cl) C (= O) O

COc1ccc2C (= CC (= O) Nc2c1OCCCCC (= O) N [C @@ H] (CCC (= O) N) C (= O) O) Nc3c (Cl) cncc3Cl

NC (= O) ACCOc1c (OCF) ccc2C (= CC (= O) Ncl2) Nc3c (Cl) cncc3Cl

COc1ccc2C (= CC (= O) Nc2c1OCCCCCC (= O) OCCN (C) C) Nc3c (Cl) cncc3Cl

C [C @@ H] (0) [C @ H] (NC (= 0) ACCOCO1c (OC (F) F) ccc2C (= CC (= O) Ncl2) Nc3c (Cl) cncc3cl) C (= O) THE

NC (= O) C [C @ H] (NC (= O) ACCOc1c (OC (F) (F) F) ccc2C (= CC (= O) N c 12) Nc3c (Cl) cn cc3Cl) C (= O) O

ACNC (C) ACCOc1c (OC (F) F) ccc2C (-CC (= O) Nc 12) Nc3c (Cl) cncc3Br

FClCCN (ACCOc2c (OC (F) (F) F) ccc3C (= CC (= O) Nc23) Nc4c (Cl) cncc4Br) Cl

COc1ccc2C (= CC (= O) Nc2c1OCCCCn3cccc3) Nc4c (Cl) cncc4Br

FCOc1ccc2C (= CC (= O) Nc2c1OCCCCn3ccnc3) Ne4c (Cl) encc4Br

FC1CCN (ACCOCO2c (OC (F) (F) F) cec3C (= CC (= O) Nc23) Nc4c (Cl) cnec4Br) Cl

COc1ccc2C (= CC (= O) Nc2c1OCCCCCn3cnoc3) Nc4c (Cl) cncc4Br

FCOc1ccc2C (= CC (= O) Nc2c1OCCCCCn3ncnn3) Nc4c (Cl) cncc4Br

COCCOCCOCCCCCOc1c (OC (F) F) ccc2C (= CC (= O) Nc12) Nc3c (Cl) cncc3Br

NCCCCCCOclc (OCF) ccc2C (= CC (= O) Nc12) Nc3c (Cl) cncc3Br

COCCN (C) CCCCCCOc1c (OC (F) (F) F) ccc2C (= CC (= O) Nc12) Nc3c (Cl) cncc3Br FC (F) Oc I ccc2C (= CC (0) Nc2c 1 OCCCCCCN3CCCCC3) Nc4c (CI ) cncc4Br COCCOCCCCGCOc 1 c (0C) ccc2C (= CC (-0) Nc 12) Nc3c (Cl) cncc3 Br NC (= 0) C0c 1 c (0C (F) (F) ccc2C (= CC (= 0 ) Nc 12) Nc3c (CI) cncc3Br COc 1 ccc2C (= CC (= 0) Nc2c IOCC (= 0) 0CC [N +] (C) (C) Nc 3 c (CI) cncc3 Br CC (C) [C @ H] (NC (= 0) COc1c (0CF) ccc2C (= CC (= 0) Ncl2) Nc3c (Cl) cncc3Br) C (= 0) 0 0C (= 0) [CH] (Cc 1 CCC ( O) CC 1) NC (= 0) C0c2c (0C (F) F) ccc3C (= CC (= 0) Nc23) Nc4c (C1) cncc4Br COc 1 ccc2 C (= CC (= 0) Nc2c1OCCCC (= 0) N [C @@ H] (C) C (= 0) 0) Nc 3c (Cl) cncc3 Br 0C (= 0) [C @ H] (Cc1ccc (0) ccl) NC (= 0) CCCO0c2c (0C ( F) (F) F) ccc3C (= CC (= 0) Nc23) Nc4c (Cl) cncc4Br 0C (= 0) C [0 @ Η] (ΝC (= 0) CCC0c1c (0CF) ccc2C (= CC (= 0 ) Nc12) Nc3c (Cl) cncc3 Br) C (= 0) 0

0C (= 0) CC [C @ H] (NC (= 0) CCC0c1c (0C (F) F) ccc2C (= CC (= 0) Nc12) N c3 c (CI.) Cncc3 Br) C (= 0) 0

COc1ccc2C (= CC (= 0) Nc2cl0CCCCC (= 0) 0CC [N +] (C) (C) C) Nc3c (Cl) cnce3Br CN (C) CCCN (C) C (= 0) ACCOOc1c (0CF) ccc2C (= CC (= 0) Ncl2) Nc3c (Cl) cncc3Br CSCC {C @ H] (NC (= 0) ACC0clc (0C (F) F) ccc2C (= CC (= 0) Ncl2) Nc3c (Cl) cncc3Br) C ( = 0) 0 0C [C @ H] (NC (= 0) ACC0cc (0C (F) (F) F) ccc2C (= CC (= 0) Nc12) Nc3c (Cl) cncc3Br) C (= 0) 0

COc1ccc2C (= CC (= 0) Nc2c10CCCCCC (-0) N [C @@ H] (Cc3ccc (0) cc3) C (= 0) 0) Nc4c (CI) cncc4Br

CSCC [C @ H] (NC (= 0) ACCOCl c (0CF) ccc2C (= CC (= 0) Nc 12) Nc3c (Cl) cncc3Br) C (= 0) 0

0C (= 0) C [C @ H] (NC (= 0)) ACCOcCl (0C (F) (F) F) ccc2C (= CC (= 0) Ncl2) Nc3c (Cl) cn cc3Br) C (/ - 0) 0

NC (= 0) CC [C @ H] (NC (= 0) ACCOc0cc (0C (F) F) ccc2C (= CC (= 0) Ncl2) Nc3c (Cl) cnc c3Br) C (= 0) 0

NC (= N) NCCCCOc c (0C (F) (F) F) ccc2C (= CC (= 0) Nc 12) Nc3c (Br) cncc3Br FC (F) Oc 1 ccc2C (= CC (= 0) Nc2cl 0CCCCN3CCC ( F) CC3) Nc4c (Br) cncc4Br FCOc1ccc2C (= CC (= 0) Nc2c1OCCCCn3ccnn3) Nc4c (Br) cncc4Br <formula> formula see original document page 120 </formula> C [C @ H] (NC (-0) COUNC0cc (PC (F) (F) F) ccc2C (= CC (= O) Nc12) Nc3c (Br) cncc3Br) C (= O) 0

CC (C [C @ H] (NC (= O)) COCOcc (OC (F) F) ccc2C (-CC (= O) Nc12) Nc3c (Br) cncc3Br) C (= 0) O

C0c1ccc2C (= CC (= O) Nc2c] OCCCCCC (= O) N [C @@ H] (Cc3ccccc3) C (= O) O) Nc4c (Br) cncc4Br

NC (-0) CC [C @ H] (NC (= O)) COCOc1c (OC (F) (F) F) ccc2C (-CC (-0) Ncl2) Nc3c (Br) cncc3Br) C (= O) O

The activity of the compounds in examples 1-14 as PDE4 inhibitors is illustrated in the following assay. The other compounds listed above, which have not been made and / or tested yet, are predicted to have activity in this assay as well.

New PDE / AK Biological Activity Test Protocol

Phosphodiesterases regulate the activity of the second messenger cyclic adenosine monophosphate (cAMP) by hydrolyzing cAMP to adenosine monophosphate (AMP). We have developed a new high production bioluminescent PDE / AK assay to measure phosphodiesterase activity. In the PDE / AK assay, AMP produced from cAMP hydrolysis by phosphodiesterase is converted to adenosine diphosphate (ADP) by adenylate kinase phosphotransferase activity (also known as ADK or myokinase). Adenylate kinase will catalyze the conversion of 1 mol of AMP and 1 mol of ATP to 2 moles of ADP. Thus conversion of AMP to ADP will result in subsequent loss of ATP. Decreasing ATP concentration can be monitored as light output using luciferase in a reaction that requires ATP to produce light. The PDE / AK assay uses luciferase, which catalyzes the light production of ATP present in the reaction mixture. The amount of light emitted is inversely proportional to the AMP level present in the reaction. Test compounds are incubated with phosphodiesterase and phosphodiesterase inhibitors which will decrease the cAMP hydrolysis rate and decrease subsequent AMP production. Thus phosphodiesterase inhibitors will decrease the conversion of ATP to ADP and the result in large light emission.

Compounds may be selected for functional potency in in vitro biochemical assays for their ability to inhibit phosphodiesterase (PDE) enzyme activity. A new coupled PDE / AK assay was used to measure the inhibitory activity of compounds in PDE isoforms. The catalytic domain of PDE4B was fused to an amino terminus hexhistidine affinity tag and purified. PDE4B enzyme was incubated with the compounds for 10 minutes. Cyclic AMP substrate, ATP and adenylate kinase were then added to the PDE enzyme mixture and incubated for 45 minutes at room temperature. A commercial ATP detection assay, Perkin Elmer's easyLite ATP detection reagent, was then added to measure the relative amount of ATP present in the reaction. After 10 minutes of incubation, the luminescent signal was dosed with Perkin Elmer Viewlux or Molecular Devices and Analyst. Roflumilast and Rolipram are the positive controls used in the assay.

The PDE / AK assay can be performed with any cCAMP dependent phosphodiesterase, and can be performed in 96, 384, or 1556-well plates. Unlike other phosphodiesterase activity assays, the PDE / AK assay does not require radioactive substrates, modified substrates, granules, or antibodies, which each have disadvantages. Specifically, the use of radioactive substrates in a phosphodiesterase activity assay requires special protocols for waste handling and disposal, and reduced production. Modified substrates add the added complexity of potential by altering binding to the phosphodiesterase catalytic site. Fluorescent modified substrates may cause fluorescence artifacts that may interfere with the interpretation of assay results. Use of granules that selectively bind to cAMP or AMP may cause additional complexity in reagent handling. Use of antibodies that selectively bind cAMP or AMP can be extremely expensive with a relatively small signal to noise ratio. Consequently, the new PDE / AK assay represents simple known, cost effective alternative methods.

Additionally, PDE / AK assay mechanisms offer advantages which make them useful for comparison to other phosphodiesterase activity assays. In conventional assays, where cAMP concentration is inversely proportional to bioluminescence output (such as Cambrex Biosciences's PDELight), phosphodiesterase catalyzes cAMP or AMP hydrolysis that is subsequently converted to ATP, consumed by a luciferase enzyme, and results at an increased bioluminescent output. A phosphodiesterase inhibitor prevents cAMP or AMP hydrolysis and consequently results in decreased bioluminescent output. However, compounds exhibiting luciferase inhibition activity should be labeled as a false positive for PDE inhibition in the standard assay. In contrast, the new PDK / AK assay does not mark luciferase inhibitors as false positive for PDE inhibition because inhibition of PDE activity would result in increased bioluminescence. However, compounds that are capable of inhibiting both PDE and luciferase would be false negatives. Compounds that inhibit adenylate kinase should be flagged as false positives in the new PDE / AK assay. Using both types of tests, and comparing the data from both, would yield a richer and more reliable data set. Accordingly, contemplated herein is a method for detecting and quantifying PDE inhibition using adenylate kinase coupled with an ATP depletion assay.

In certain embodiments, said method comprises the steps of:

.1. A first incubation of PDE or an isolated isoform thereof with a compound to be tested;

.2. Addition of ATP, cAMP, and AK substrates;

.3. A second incubation of said PDE;

.4. Coupling of means for reading the depletion of

ATP; and

.5. Reading.

In additional embodiments, said first incubation is for about 5 to about 15 minutes; in however additional embodiments, said first incubation is for approximately 10 minutes.

In additional embodiments, said second incubation takes place for longer than approximately 30 minutes; once again in additional embodiments, said sufficient length of time is between about 30 minutes and about one hour; even in additional achievements, the sufficient length of time is approximately 45 minutes.

In further embodiments, said means for reading is a luciferase assay. In still further embodiments, said luciferase assay is a Perkin Elmer easyLite assay.

In further embodiments, said reading is taken on a machine to detect a luminescent signal. Still in additional embodiments, said machine is selected from the group consisting of a Perkin Elmer Viewlux, Molecular Devices Acques, and Molecular Devices Analyst.

Results are shown below in Table 1.

TABLE 1. BIOLOGICAL ACTIVITY <table> table see original document page 125 </column> </row> <table>

IN VIVO TEST Dry Eye Induced by Lacrimal Gland Inflammation in Rabbits

A more detailed description of the assay used here can be found in Naglehout, TJ et al. , 0 05, "Preservation of Tear Film Integrity and Inhibition of Corneal Injury by Dexamethasone in a Rabbit Model f Lacrimal Gland Inflammation-Induced Dry Eye", J. Ocular Pharm.Ther., 21: 2. 139-148, the description of which is hereby incorporated by reference as if written herein in its entirety.

Dry Eye Initiation and Treatment Rabbits (n = 4 / group) were randomized into treatment groups and into topically dosed BID with the maxidex vehicle or test drug that begins one day prior to dry eye initiation. Each rabbit received bilateral injections of the saline or ConA Iacrimal gland (300 pg / 30 μΐ) and the topical ocular dose was continued on BID throughout the study.

Corneal Spot

Desiccation was initiated 1-2 hours following injection of the tear gland by placing conscious rabbits in the environmental chamber (10-15% humidity / 72 ° F). After 72 consecutive hours of exposure to this dry environment, the animals were anesthetized and sutures were placed on each upper and lower eyelid and raised to form a horny / conjunctival cup. Methylene blue dye (1 mL, 1% in dH20) was added to the body for three minutes and the excess removed by washing with 200 mL BSS®. The contralateral eye was then stained using the same procedure. Rabbits were euthanized immediately following the staining procedure and the eyes were excised. The corneas were isolated with a trephine and the 9.5-mm corneal perforator was placed in 2 mL of saturated sodium acetone / sulfate (7: 3, vol / vol). The absorbance of the extracted dye was determined at 660 nm.

Tear Dissolve Time (TBUT)

TBUT was determined in a separate group of treated animals. TBUT was determined by instilling the 5 µl sodium fluorescein at the end and manually blinking the eyelids to distribute the fluorescein within the tear film. Under observation of the cutting lamp, the eye was held open and time by one or more black dots or scratches appeared on the pre-corneal tear film was recorded. Rabbits were euthanized for 3 days following ConA injection.

Data reported as NT refers to the example that is not being tested.

TABLE 2. IN VIVO ACTIVITY <table> table see original document page 127 </column> </row> <table>

From the foregoing description, one skilled in the art can readily ascertain the essential features of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to suit various uses and conditions.

Claims (32)

PDE4 inhibition method, characterized by contacting PDE4 with a compound of the formula IV (formula) (IV) or a salt, ester, or prodrug thereof, where: X3 is (CR18 R19); R 1 and R 2 are independently selected from the group consisting of - (CH 2) SG 1 G 2 G 3, acyl, acylalkyl, carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, ether, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen and hydroxyalkyl, any of which may be optionally substituted; s is 1-8; G1 is selected from the group consisting of alkoxy, amino, starch, carbonyl, hydroxy, ether, amino acid, and zero; G 2 is selected from the group consisting of alkyl, alkoxy, amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino, guanidine, an amino acid and zero, any of which may optionally be substituted; G 3 is selected from the group consisting of alkyl, alkoxy, amino, hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate, phosphoamide and zero, any of which may optionally be substituted; R3 and R4 are independently selected from the group consisting of hydrogen, halogen, alkoxy and lower alkyl; R5 is selected from the group consisting of CR8R9) mW (CR10R11) n-e- (CR12R13) p-; W is selected from the group consisting of O, N (Rv), C (O) N (Rv), and SOq; m, n, and q are independently 0, 1 or 2; p is 1 or 2; R 6 is selected from the group consisting of carboxyl, alkylcarboxy, starch, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, acyl and hydroxamic acid, and any of which may optionally be substituted; R 7, R 8, R 9, R 10, R 11, R 12 and R 13 are each independently selected from the group consisting of hydrogen and optionally substituted lower alkyl; R 14 is selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, hydroxyalkyl, aminoalkyl and haloalkyl; and R 18 and R 19 are each independently selected from the group consisting of hydrogen, halogen, lower alkyl, haloalkyl, alkoxy, haloalkoxy, amino, aminoalkyl, aminoalkoxy and a bond. A method of treating a PDE4-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula IV (IV) or a salt, ester, or prodrug of the drug. same, where: X 3 is (CR18R19); R1 and R2 are independently selected from the group consisting of - (CH2) SG1G2G3, acyl, acylalkyl, carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, ether, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen and hydroxyalkyl, any of which may optionally be substituted; s is 1-8; G1 is selected from the group consisting of alkoxy, amino, starch, carbonyl, hydroxy, ether, one amino acid and zero; G 2 is selected from the group consisting of alkyl, alkoxy, amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino, guanidine, an amino acid and zero, any of which may optionally be substituted; G 3 is selected from the group consisting of alkyl, alkoxy, amino, hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate, phosphoamide and zero, any of which may optionally be substituted; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, alkoxy and lower alkyl; R5 is selected from the group consisting of (CR8R9) mW (CR10R11) n and - (CR12R13) p-; W is selected from the group consisting of O, N (R7), C (O) N (R7) and SOq; m, n, and q are independently 0, 1 or 2; ρ is 1 or 2; R 6 is selected from the group consisting of carboxyl, alkylcarboxy, starch, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, acyl and hydroxamic acid, any of which may optionally be substituted; R 7, R 8, R 9, R 10, R 11, R 12 and R 13 are each independently selected from the group consisting of hydrogen and optionally substituted lower alkyl; R 14 is selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, hydroxyalkyl, aminoalkyl and haloalkyl; and R 18 and R 19 are each independently selected from the group consisting of hydrogen, halogen, lower alkyl, haloalkyl, alkoxy, haloalkoxy, amino, aminoalkyl, aminoalkoxy and a bond. Method according to claim 2, characterized in that said PDE4-mediated disease is an ophthalmic disease. Method according to claim 3, characterized in that said ophthalmic disease is selected from the group consisting of dry eye, glaucoma, corneal neovascularization, optic neuritis, Sjogren's syndrome, retinal ganglion degeneration, ocular ischemia, retinitis. retinopathy, uveitis, eye photophobia and inflammation and pain associated with acute injury to eye tissue. Method according to claim 2, characterized in that said PDE4 is subtype PDE4B. 6 Method of treating a PDE4-mediated disease, comprising administering: a. a therapeutically effective amount of a compound of formula IV <formula> formula see original document page 132 </formula> OR a salt, ester, or prodrug thereof where <formula> formula see original document page 132 < / formula>); R 1 and R 2 are independently selected from the group consisting of - (CH 2) 3G1G2G3, acyl, acylalkyl, carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, ether, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, hydrogen and hydroxyalkyl, some of which may optionally be substituted; see 1-8; G1 is selected from the group consisting of alkoxy, amino, starch, carbonyl, hydroxy, ether, one amino acid and zero; G 2 is selected from the group consisting of alkyl, alkoxy, amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino, guanidine, an amino acid and zero, any of which may optionally be substituted; G 3 is selected from the group consisting of alkyl, alkoxy, amino, hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate, phosphoamide and zero, any of which may optionally be substituted; R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, alkoxy and lower alkyl; R5 is selected from the group consisting of (CR8R9) mW (CR10R11) n and - (CR12R13) p-; W is selected from the group consisting of O, N (R7), C (O) N (Rv) and SOq; m, n, and q are independently 0, 1 or 2; ρ is 1 or 2; R 6 is selected from the group consisting of carboxyl, alkylcarboxy, starch, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, acyl and hydroxamic acid, any of which may optionally be substituted; R 7, R 8, R 9, R 10, R 11, R 12 and R 13 are each independently selected from the group consisting of hydrogen and optionally substituted lower alkyl; R 14 is selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, hydroxyalkyl, aminoalkyl and haloalkyl; and R18 and R19 are each independently selected from the group consisting of hydrogen, halogen, lower alkyl, haloalkyl, alkoxy, haloalkoxy, amino, aminoalkyl, aminoalkoxy and a bond; and b. another therapeutic agent. 7. COMPOUND, characterized in that it comprises the structural formula V (formula) (V) R1 and R2 are independently selected from the group consisting of - (CH2) sG1G2G3, acyl, acylalkyl, carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, ether, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkyl, heterocycloalkyl, amino hydroxyalkyl, some of which may optionally be substituted; s is 1-8; G1 is selected from the group consisting of alkoxy, amino, starch, carbonyl, hydroxy, ether, one amino acid and zero; G 2 is selected from the group consisting of alkyl, alkoxy, amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino, guanidine, an amino acid and zero, any of which may optionally be substituted; G 3 is selected from the group consisting of alkyl, alkoxy, amino, hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate, phosphoamide and zero, any of which may optionally be substituted; R5 is selected from the group consisting of- (CR8R9) mW (CR10R11) n and - (CR12R13) p-; W is selected from the group consisting of O, N (R7), C (O) N (Rv) and SOq; m, η, and q are independent 0, 1 or 2; ρ is 1 or 2; R 6 is selected from the group consisting of carboxyl, alkylcarboxy, starch, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, acyl and hydroxamic acid, any of which may optionally be substituted; R 7, and R 14 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, hydroxyalkyl, haloalkyl and aminoalkyl; R 8, R 9, R 10, R 11, R 12 and R 13 are each independently selected from the group consisting of hydrogen and optionally substituted lower alkyl; and R19 is selected from the group consisting of hydrogen, halogen, lower alkyl and haloalkyl. A compound according to claim 7, characterized in that R 7 and R 14 are independently selected from the group consisting of hydrogen, halogen and optionally substituted lower alkyl. A compound according to claim 8, wherein R 6 is selected from the group consisting of aryl and heteroaryl, each of which may optionally be substituted. Compound according to claim 9, characterized in that R19 is hydrogen. A compound according to claim 10, characterized in that R 6 is selected from the group consisting of phenyl, pyridine, pyrimidine, pyridazine and pyrazine, any of which may optionally be substituted. Compound according to claim 11, characterized in that R14 is hydrogen. Compound according to claim 12, characterized in that: R5 is - (CR8R9) mW (CR10R11) n-; m and η are both 0; W is N (R7); and R7 is hydrogen. Compound according to claim 13, characterized in that R2 is lower alkyl. A compound according to claim 14, characterized in that: R1 is selected from the group consisting of - (CH2) 3G1G2G3, lower alkyl, cycloalkyl, cycloalkylalkyl and heterocycloalkyl, some of which may optionally be substituted; s is 1-6; G1 is selected from the group consisting of amino, starch and zero; G 2 is selected from the group consisting of alkoxy, aryl, halo, heterocycloalkyl and zero, any of which may optionally be substituted; G3 is selected from the group consisting of alkyl, carboxyl and zero, any of which may optionally be substituted. Compound according to claim 15, characterized in that R2 is methyl. Compound according to claim 16, characterized in that R6 has a formula selected from the group consisting of <formula> formula see original document page 137 </formula> R20, R21, R22, R23 and R24 are independently selected. from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, amino and carboxyl. 18. COMPOUND, characterized in that it comprises the structural formula VI or a salt, ester or prodrug thereof, wherein: R1 and R2 are independently selected from the group consisting of: in - (CH2) sG1G2G3, acyl, acylalkyl, carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, heteroalkyl, cycloalkyl, heteroalkyl, cycloalkyl aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl and hydroxyalkyl, some of which may optionally be substituted; s is 1-8; G1 is selected from the group consisting of alkoxy, amino, starch, carbonyl, hydroxy, ether, one amino acid and zero; G 2 is selected from the group consisting of alkyl, alkoxy, amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino, guanidine, an amino acid and zero, any of which may optionally be substituted; G 3 is selected from the group consisting of alkyl, alkoxy, amino, hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate, phosphoamide and zero, any of which may optionally be substituted; R20 and R24 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, amino and carboxyl. Compound according to claim 18, characterized in that R20 and R24 are independently selected from the group consisting of hydrogen, halogen and lower alkyl. A compound according to claim 19, characterized in that R 2 is lower alkyl. A compound according to claim 20, characterized in that: R1 is selected from the group consisting of - (CH2) sG1G2G3, lower alkyl, cycloalkyl, cycloalkylalkyl and heterocycloalkyl, some of which may optionally be substituted; s is 1-6; G1 is selected from the group consisting of amino, starch and zero; G 2 is selected from the group consisting of alkoxy, aryl, halo, heterocycloalkyl and zero, any of which may optionally be substituted; and G3 is selected from the group consisting of alkyl, carboxyl and zero, any of which may optionally be substituted. Compound according to claim 21, characterized in that R2 is methyl. 23. COMPOUND, characterized in that it comprises structural formula VII or a salt, ester, or prodrug thereof, wherein: R1 and R2 are independently selected from the group consisting of: in - (CH2) sG1G2G3, acyl, acylalkyl, carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, heteroalkyl, cycloalkyl, heteroalkyl, cycloalkyl aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl and hydroxyalkyl, some of which may optionally be substituted; s is 1-8; G1 is selected from the group consisting of alkoxy, amino, starch, carbonyl, hydroxy, ether, one amino acid and zero; G 2 is selected from the group consisting of alkyl, alkoxy, amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino, guanidine, an amino acid and zero, any of which may optionally be substituted; G 3 is selected from the group consisting of alkyl, alkoxy, amino, hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate, phosphoamide and zero, any of which may optionally be substituted; R20 ， R22 and R24 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, amino and carboxyl. Compound according to claim 23, characterized in that R, R, and R are independently selected from the group consisting of hydrogen, halogen, and lower alkyl. Compound according to claim 24, characterized in that R2 is lower alkyl. A compound according to claim 25 comprising: R1 is selected from the group consisting of - (CH2) sG1G2G3, lower alkyl, cycloalkyl, cycloalkylalkyl and heterocycloalkyl, some of which may optionally be substituted; s is 1-6; G1 is selected from the group consisting of amino, starch and zero; G 2 is selected from the group consisting of alkoxy, aryl, halo, heterocycloalkyl and zero, any of which may optionally be substituted; and G3 is selected from the group consisting of alkyl, carboxyl and zero, any of which may optionally be substituted. Compound according to claim 26, characterized in that R2 is methyl. 28. COMPOUND, characterized in that it is selected from the group consisting of Examples 1 to 14. COMPOUND OR COMPOSITION according to claim 7 for use as a medicament. A compound according to claim 7, characterized in that it is for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by inhibition of PDE4. A compound according to claim 30, characterized in that said PDE4 is the subtype PDE4B. PHARMACEUTICAL COMPOSITION, characterized in that it comprises a compound according to claim 7 together with a pharmaceutically acceptable carrier.